Frontline Therapy Approach for Stage 4 GEJ Cancer

Manish A. Shah, MD:In terms of frontline chemotherapy, most patients would really receive a doublet combination of a platinum and fluoropyrimidine. However, there are patients who may be good candidates for a 3-drug combination. There was actually a Cochrane Review that looked at 3 drugs versus 2 drugs. This was in the era when there were more data for epirubicin, platinum 5-FU, and more patients in that review actually had that treated regimen than another.

And the upshot of that review was that if you were physically able to receive the 3-drug regimen, then you would have a better outcome by starting with a 3-drug regimen instead of a 2-drug regimen. But that was also done in an era when most patients received only one line of therapy, not multiple lines of therapy. And that was an argument that actually our Asian colleagues, particularly from Korea and Japan, would make. They said that they use a doublet in the first-line setting because 80% or more of their patients get a second-line or third-line drug, and that wasn’t the case in the West.

And so, as you know, patients in Korea and Japan, they have survivals for gastric and GE junction cancer that are far superior to what we see in the West. Part of that might be biology, in terms of the disease subtype that they see, but part of it might be the way they are able to manage the patients with toxicity to trigger a regimen that is less toxic. And if you’re able to get to a second-line agent, then you’re able to distribute the toxicity across a longer period of time.

The current 3-drug regimen that is having more credence now incorporates a taxane in the first-line setting. So, it’s based on a study of DCF—docetaxel, cisplatin, 5-FU—versus CF. And that study actually wasn’t that positive and proved docetaxel in the first-line setting was really quite a toxic regimen. So, since that publication, there have been efforts to figure out ways to administer the 3 drugs by mitigating toxicity.

We created a regimen called the modified DCF regimen, which is a 2-day 5-FU infusion plus reduced doses of docetaxel and cisplatin. And our data were actually evaluated in a randomized phase II setting multicenter. Patients who received the DCF regimen had a substantial survival of 16 months, which was really quite improved, quite notable.

The other regimen that’s very similar is the FLOT regimen developed in Germany. That is 5-FU as a 24-hour infusion of oxaliplatin and Taxotere (docetaxel). And I think what we know is that these 3-drug regimens are less toxic than the parent DCF regimen, but they are still toxic. So, they’re not for everybody. In select patients, you might consider a 3-drug regimen. I think in the setting of metastatic disease, if you’re able to get a 3-drug regimen in the first-line setting, you’re also more likely to not be able to get a 2-drug regimen and then a second-line agent. So, I’m not certain that there’s that much of an advantage to starting with a 2-drug regimen.

The last point I’d make is that as we get more drugs approved in gastric cancer—so pembrolizumab is approved in the third-line setting—LONSURF (trifluridine/tipiracil) will likely get approved as well based on the TAGS study. We have irinotecan, we have Taxol (paclitaxel)/Cyramza (ramucirumab), platinum 5-FU. We’re getting to a point where we’re saturating our options. And so, if we do what we’ve historically done, a 2-drug regimen followed by another, let’s say Taxol/Cyramza in the second-line setting and then pembrolizumab in the third-line setting, then patients may not actually be able to get the irinotecan or LONSURF. So, then in that setting, adding a third drug in the first line to actually give patients the opportunity to have more drugs might be a consideration.

Transcript edited for clarity.

A 54-Year-Old Man With Stage IV Gastroesophageal Junction Cancer

January 2018

• A 54-year-old man presented to his PCP complaining of loss of appetite, indigestion, and dysphagia lasting approximately 4 months and subsequent 12-lb weight loss
• PE: patient was pale-appearing; abdominal auscultation
• Notable laboratory findings:
  • HB 10.8 g/dL
  • LFT WNL
  • CEA, 18.4 ng/mL
• Upper GI endoscopy with endoscopic ultrasound showed a hypoechoic mass, approximately 3.3 cm, located in the gastric cardia and extending to the gastroesophageal junction, infiltrating the gastric wall into the subserosal mucosa
• Biopsy results confirmed poorly differentiated gastric adenocarcinoma
  • Molecular testing; HER2(-), MSI-stable, PD-L1 expression 0%
• CT of chest, abdomen, and pelvis indicated liver mets confirmed
• Staging; GEJ adenocarcinoma T4bN0M1, unresectable, Siewert II
• PS; ECOG 0
• After multidisciplinary assessment, the patient was started on FOLFOX
• Three-month follow-up
  • Imaging showed a partial response to systemic therapy
  • Patient complained of mild neuropathy; oxaliplatin was discontinued after 4 cycles of chemotherapy

July 2018

• Patient reports increasing fatigue
• CT imaging at 6 months shows metastatic spread to multiple subcarinal and right hilar lymph nodes; increased size in two of the liver lesions
• PS; ECOG 1
• Patient is motivated to try another systemic therapy
• The patient is planned to start therapy with paclitaxel/ramucirumab