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Advanced Gastric Cancer

CE / CME

Cases and Challenges in the Optimal Treatment of Advanced Gastric Cancer

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: April 27, 2023

Expiration: April 26, 2024

Steven Maron
Steven Maron, MD
CME/CE Information

Activity

Progress
1
Course Completed

HER2-Negative mGC

Historically, treatment of advanced GC included platinum-based chemotherapy regimens and was associated with poor outcomes and progression or death within a year.5 The phase III CheckMate 649 trial compared treatment with the prior standard chemotherapy vs chemotherapy plus the anti–PD-1 monoclonal antibody (mAb) nivolumab. Chemotherapy regimens studied were XELOX (oxaliplatin/capecitabine) and FOLFOX (oxaliplatin/leucovorin/5-fluorouracil).5,6 Patients were stratified by CPS, a measure of PD-L1 expression. Patients in the trial had previously untreated, unresectable, advanced or metastatic HER2-negative gastric, GEJ, or esophageal adenocarcinoma (N = 1581). As seen in Figure 1, addition of nivolumab to standard chemotherapy improved OS, with a larger effect seen in patients with PD-L1 CPS ≥5.7 

Based on the results of CheckMate 649, nivolumab combined with platinum/fluoropyridamine chemotherapy is the recommended first-line treatment for HER2-negative advanced or mGC in guidelines from the National Comprehensive Cancer Networks (NCCN) and American Society for Clinical Oncology (ASCO).4,8 Nivolumab combined with platinum/fluoropyridamine chemotherapy is indicated for adults with advanced or metastatic GC, GEJ cancer, and esophageal adenocarcinoma.9 In NCCN guidelines, the combination is preferred with PD-L1 CPS ≥5, but also has value for patients with CPS <5.4

Figure 1. HER2-Negative mGC: Chemotherapy ± Nivolumab in Initial Therapy (CheckMate-649)7

The KEYNOTE-859 compared pembrolizumab plus chemotherapy versus chemotherapy alone (5-fluorouracil/cisplatin or capecitabine/oxaliplatin) as first-line treatment of HER2-negative advanced gastric/GEJ cancer. Patients were stratified by PD-L1 CPS ≥1 versus CPS <1, and the primary endpoint was OS.38 Median follow-up time in the study was 31 months. All patients were confirmed HER2-negative; in each cohort, about 5% were MSI-high, and 78% had PD-L1 CPS ≥1.38  Addition of pembrolizumab was associated with a 22% reduction in risk of death (HR: 0.78; 95% CI: 0.70-0.87; P <.0001). Addition of pembrolizumab also was associated with improved PFS, higher objective response rate, and longer duration of response.38 These results are not reflected in current guidelines, but it is reasonable to consider pembrolizumab or nivolumab added to chemotherapy for patients with HER2-negative advanced gastric/GEJ cancer.

For patients with advanced or metastatic esophageal/GEJ adenocarcinoma, ASCO recommends nivolumab plus chemotherapy for patients with PD-L1 CPS ≥5 or pembrolizumab plus chemotherapy for PD-L1 CPS ≥10 based on phase III KEYNOTE-590.8,10 In KEYNOTE-590, patients with previously untreated locally advanced or metastatic esophageal cancer or Siewert type 1 gastroesophageal cancer received pembrolizumab or placebo with fluoropyrimidine and platinum-based chemotherapy. Progression-free survival (PFS) was improved with the addition of pembrolizumab to chemotherapy when PD-L1 CPS ≥10.8,10  

HER2-Positive Advanced GC

The benefit of HER2-directed therapy for HER2-positive advanced gastric or GEJ cancer was demonstrated in results from TOGA, a phase III trial that compared the addition of trastuzumab to chemotherapy vs chemotherapy alone. The addition of trastuzumab to fluoropyrimidine plus platinum chemotherapy was associated with 26% reduction in risk of death (HR: 0.74; 95% CI: 0.60-0.91; P = .0046), which was highly significant.11 Subsequently, trastuzumab plus chemotherapy became a standard of care for patients with HER2-positive GC. 

Today, the updated standard first-line option is pembrolizumab plus trastuzumab/chemotherapy (fluoropyrimidine plus platinum), based on results seen in KEYNOTE-811. This phase III study included 692 patients with HER2-positive advanced gastric or GEJ cancer and no prior therapy in the advanced setting. At the time of the first interim analysis, objective response rate and duration of response were available for the first 264 patients who were randomized (Table 2).11 Significantly more patients achieved response, leading to approval of the combination as first-line treatment.12,13 Also notable was that the safety profile was similar between treatment arms, with no unexpected safety concerns associated with pembrolizumab.12 In guidelines from NCCN and ASCO, the combination with pembrolizumab is the preferred option for patients with HER2-positive advanced GC, independent of PD-L1 CPS level.8

Table 2: HER2-Positive mGC: Pembrolizumab + Trastuzumab + Chemotherapy in Initial Therapy (KEYNOTE-811)12

 

Expert Insights From Dr Maron: Responses to first-line addition of pembrolizumab to chemotherapy + trastuzumab in HER2-positive advanced GC

 

 

Figure 2 summarizes the preferred approach to initial therapy for patients with HER2-negative and HER2-positive advanced GC or GEJ.4 For either, incorporation of an anti-PD-1 immune checkpoint inhibitor (ICI) is now standard practice and improves outcomes for patients. Nivolumab is an option in GC for patients with CPS ≥1, although evidence is stronger for CPS ≥5. Pembrolizumab is an option for those with GEJ adenocarcinoma with CPS ≥1, although evidence is stronger for CPS ≥10.8

Figure 2. Preferred Initial Therapy for Advanced GC4,8

In approximately what percentage of patients being treated with an ICI are endocrine system immune-related adverse events (irAEs) reported?

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