Factors Affecting First-Line ICI Choice in HER2-Negative Gastric Cancer

The addition of an immune checkpoint inhibitor to first-line chemotherapy has become standard practice for treating patients with HER2-negative metastatic gastric or gastroesophageal junction (GEJ) cancer. There are several available checkpoint inhibitors to use in this setting, including nivolumab (Opdivo), pembrolizumab (Keytruda), and tislelizumab (Tevimbra).

In a recent Case-Based Roundtable event, Zev Wainberg, MD, led a discussion covering the practical and clinical factors to consider when choosing among these immunotherapies. Wainberg is a medical oncologist and GI oncology specialist at the David Geffen School of Medicine at UCLA.

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CASE SUMMARY

• 60-year-old man with abrupt 10-pound weight loss, dyspepsia, bloating after meals, and loss of appetite, with all symptoms worsening over the past 3 months
• Family history: father deceased at age 50 (gastric cancer)
• Past medical history: overweight, hypertension
• Esophagogastroduodenoscopy showed 2-cm protruding mass in the body of the stomach, without ulceration
• Biopsy revealed poorly differentiated adenocarcinoma
• HER2/neu negative, mismatch repair proficient/microsatellite stable, PD-L1 combined positive score (CPS) of 5, and Claudin 18.2 expression below 75%
• CT of the abdomen and chest revealed a gastric polypoid mass measuring 4.8 cm and 2 lung lesions measuring 1.8 cm and 1.1 cm, with lung biopsy confirming metastatic adenocarcinoma consistent with a gastric primary
• The diagnosis was stage IV gastric adenocarcinoma
• The patient was started on nivolumab (Opdivo) plus FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin)

EVENT RECAP

Wainberg opened the discussion by noting that at least half of patients with metastatic gastric or GEJ cancer receive only 1 line of therapy, underscoring the importance of selecting the optimal first-line regimen using tools such as biomarkers.

The group then discussed the inconsistently of biomarker testing in practice. One participant said her institution does not automatically run the full panel and that she has to manually request HER2, MMR, CPS, and Claudin 18.2 testing from her pathology group. Another participant described a similar struggle in his practice, noting that even when testing is sent to third-party labs such as Caris or Tempus, tissue can be delayed or lost, despite his preference for reflexive testing of all 4 markers. Wainberg acknowledged that even at UCLA, while HER2 and PD-L1 testing tend to be automatic, he still has to remind colleagues to order microsatellite instability–high and Claudin 18.2 testing.

Participants next shared what their preferred treatment option was for the patient case. Overall, there was a split between adding nivolumab or pembrolizumab to chemotherapy, with only 1 attendee choosing tislelizumab. An attendee explained his pembrolizumab preference was driven primarily by familiarity and logistics within his practice, rather than any perceived efficacy advantage. Another participant said he favors nivolumab in part because of dosing flexibility, administering it every 2, 3, or 4 weeks to better synchronize with chemotherapy.

The case patient was ultimately started on nivolumab plus FOLFOX, a regimen studied in CheckMate 649 (NCT02872116). Patients in that study were randomized to nivolumab plus chemotherapy vs chemotherapy alone in first-line HER2-negative advanced or metastatic gastric, GEJ, and esophageal adenocarcinoma. Chemotherapy was either FOLFOX or CapeOX (capecitabine, oxaliplatin).

Results from CheckMate 649 showed that at a minimum follow-up of 60.1 months, the median overall survival (OS) was 14.4 months with nivolumab plus chemotherapy vs 11.1 months with chemotherapy alone in patients with a CPS of 5 or higher (HR, 0.71; 95% CI, 0.61-0.81); the 5-year OS rates were 16% vs 6%, respectively. Median progression-free survival (PFS) in this subgroup was 8.3 months vs 6.1 months (HR, 0.71; 95% CI, 0.61-0.82). Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 60% of patients in the nivolumab arm vs 45% of patients receiving chemotherapy alone.¹

Wainberg also reviewed the KEYNOTE-859 (NCT03675737) study of pembrolizumab in patients with advanced HER2-negative gastric or GEJ cancer. Among patients who received pembrolizumab plus chemotherapy the median OS was 13.0 months vs 11.4 months with chemotherapy alone in the CPS of 1 or higher population (HR, 0.74; 95% CI, 0.66-0.84); the median PFS was 6.9 vs 5.6 months, respectively (HR, 0.72; 95% CI, 0.64-0.82). Grade 3 to 5 TRAEs occurred in 59.4% vs 51.3% of patients, respectively.²

Wainberg finished his data review with a recap of tislelizumab results from the RATIONALE-305 (NCT03777657) trial, which used tumor area positivity (TAP) scoring rather than CPS to assess PD-L1 expression. The study showed that, in patients with advanced gastric or GEJ cancer, tislelizumab plus chemotherapy produced a median OS of 16.4 months vs 12.8 months with chemotherapy alone in the PD-L1 TAP 5% or higher population (HR, 0.71; 95% CI, 0.59-0.86); the median PFS of 7.2 vs 5.9 months respectively (HR, 0.69; 95% CI, 0.57-0.84). Grade 3 or higher events TRAEs occurred in 54.0% vs 49.8% of patients, respectively.³

Wainberg characterized the 3 trials as producing fairly interchangeable results and said the decision in his own practice typically comes down to familiarity and contract termsrather than any clinically meaningful difference in outcomes. A participant agreed, noting that his choice of checkpoint inhibitor depends on which agent has the most favorable contract terms at a given time, and another mentioned that she follows formulary pathways that effectively dictate which checkpoint inhibitor she uses for a given patient.

The inconsistency of PD-L1 testing itself was also discussed as another factor affecting treatment selection. A participant explained that he does not fully trust CPS scoring because he has seen patients with a CPS below 1 preoperatively return with a markedly higher score after surgery. Another participant described an experience in which 2 different pathology groups returned discordant CPS results, 1 that was below 5 and 1 that was closer to 10, on the same patient. Wainberg agreed that immunohistochemical PD-L1 testing remains a subjective and inconsistent biomarker, particularly with TAP scoring, which relies on visual estimation rather than formal cell counting.

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REFERENCES:

1. Janjigian YY, Shitara K, Moehler MH, et al. Five-year outcomes from CheckMate 649: first-line nivolumab plus chemotherapy versus chemotherapy in advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma. Ann Oncol. Published online February 11, 2026.

2. Rha SY, Wyrwicz LS, Weber PEY, et al. Pembrolizumab plus chemotherapy as first-line therapy for advanced gastric or gastroesophageal junction cancer: final analysis of the phase 3 KEYNOTE-859 study. J Clin Oncol. 2025;43(suppl 16):4036.

3. Cruz-Correa M, Xu R, Bai Y, et al. Tislelizumab plus chemotherapy as first-line treatment for advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase 3 RATIONALE-305 study. Adv Ther. 2026;43(1):165-183.