Considerations for Therapy in Gastric Cancer


Daniel Catenacci, MD, discusses initial considerations for treatment in patients with microsatellite instability-high/stable, HER2-positive/negative gastric cancer and touches on second-line treatment options.

Daniel Catenacci, MD: Assuming that the patient was HER2-positive but microsatellite stable, as opposed to MSI [microsatellite instability]-high but HER2-negative, if they were HER2-positive the standard of care of course based on the ToGA study is to start with chemotherapy plus trastuzumab. And although the study was using cisplatin and fluoropyrimidine, the trend and tendency for all of us is to exchange the cisplatin with oxaliplatin because it’s better tolerated, and well recognized and accepted at this point.

The regimen could be with capecitabine and oxaliplatin plus trastuzumab, as in this patient. Or, it could be with FOLFOX [folinic acid, fluorouracil and oxaliplatin] chemotherapy, particularly in the esophageal cancers where they can’t swallow very well, and trying to swallow capecitabine pills is challenging, whereas FOLFOX [folinic acid, fluorouracil and oxaliplatin] is very well tolerated. And the dosing of the trastuzumab can be adjusted to be every other week.

In this case the patient did receive capecitabine and oxaliplatin, and did have some difficulty with the toxicity, particularly from what sounds like the capecitabine with diarrhea, and despite dose modification was having challenges here. One might consider at that point also changing to a FOLFOX [folinic acid, fluorouracil and oxaliplatin] backbone because that’s generally better tolerated as well with respect to the diarrhea, and you could continue the patient on an active effective therapy with trastuzumab at first line.

However, we will eventually get resistance to our first-line therapy, and we would be faced with changing to next-line therapy at some point. The median progression-free survival [PFS] is around 6 to 7 months with first-line chemotherapy plus trastuzumab, and we would be considering second-line agents at that time.

This patient got pembrolizumab in the second line, because the notion was that they were HER2-positive and MSI-high, and they got trastuzumab first line and pembrolizumab in second line. But a more likely scenario of a HER2-positive microsatellite stable patient, after failing first-line chemotherapy plus trastuzumab, the standard second-line options would be to consider chemotherapy plus ramucirumab. That’s based on the RAINBOW study, a phase 3 study that randomized patients to paclitaxel with or without ramucirumab in a placebo-controlled study. There was a clear benefit in response rate from the low teens to almost 30% response rate, improved progression-free survival, and improved overall survival.

My preference has been to consider an irinotecan-based second-line therapy because many patients who start with oxaliplatin-based first-line therapy get neuropathy over the first-line therapy. Continuing in second line with another neurotoxic agent like paclitaxel, when you have other alternatives like irinotecan, which is not neurotoxic, makes more sense to me to switch to irinotecan-based therapies.

In addition to that we have a number of patients getting taxane-based therapy as perioperative therapy, either with FLOT [fluorouracil, folinic acid, oxaliplatin, docetaxel] or with carbo-Taxol [carboplatin, paclitaxel]. And many patients who have relatively quick recurrences within 6 to 12 months, starting again with paclitaxel as their second line or agent, makes little sense to me in that situation. We’ve been using FOLFIRI [folinic acid, fluorouracil, irinotecan] with ramucirumab. There are some retrospective data supporting that. It’s actually in the NCCN [National Comprehensive Cancer Network] guidelines as of January of this year, 2020, based on those data. And at ASCO [the American Society of Clinical Oncology annual meeting] 2020 a randomized phase 2 study out of Germany reported that FOLFIRI [folinic acid, fluorouracil, irinotecan] with ramucirumab versus paclitaxel with ramucirumab is quite similar. It trended to better in all-comers, and certainly trended to better in those with prior taxane exposure and in perioperative or first-line treatment. Chemotherapy plus ramucirumab is a standard approach in the second-line setting for HER2-positive or HER2-negative patients.

Transcript edited for clarity.

Case: A 71-Year-Old Man With HER2+ Gastric Cancer

Initial Presentation

  • A 71-year-old man complained of a 3-month history of abdominal pain and bloating, a sensation of fullness
  • PMH: HTN, medically controlled; colonoscopy at age 53 was unremarkable; no family history of cancer
  • PE: patient appeared tired, abdominal distention; otherwise unremarkable

Clinical Workup

  • Labs: Hb 9.7 g/dL, plt 111 x 109/L; other lab values WNL
  • Upper endoscopy with biopsy: showed an ulcerative lesion 5.8 cm mass in the cardia of the stomach; biopsy confirmed gastric adenocarcinoma
  • CT of chest/abdomen/pelvis confirmed a 5.8 cm lesion with indistinct margins in the cardia of the stomach; 2 suspicious hepatic lesions
  • EUS: gastric cancer lesion confirmed invasion of the muscularis propria
  • Mutational testing: MSI high, PD-L1 0%, HER2 3+ by IHC
  • Stage IV gastric adenocarcinoma; ECOG 2


  • He was started on XELOX/CAPOX + trastuzumab
    • Dose reduced due to grade 2 diarrhea; unable to control after 4 cycles; discontinued treatment
  • Treatment initiated with a pembrolizumab
    • After 24-months of treatment without progression of disease pembrolizumab was discontinued
  • The patient was started on trastuzumab deruxtecan; repeat HER2 expression testing was not indicated
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