Last updated January 6, 2023

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer

Treatment

First-line Therapy

Recommendation 1.1

For HER2-negative patients with gastric adenocarcinoma and PD-L1 combined positive score (CPS) ≥5, first-line therapy with nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy is recommended. (EB, B, M, S)
Qualifying statements:
  • For HER2-negative patients with gastric adenocarcinoma and PD-L1 CPS 1–5, first-line therapy with nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy may be considered on a case-by-case basis.
  • For patients with gastric adenocarcinoma and PD-L1 CPS 0, first-line therapy with fluoropyrimidine- and platinum-based chemotherapy, without the addition of nivolumab, is recommended.
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Recommendation 1.2

For HER2-negative patients with esophageal or GEJ adenocarcinoma, first-line therapy with nivolumab for patients with PD-L1 CPS ≥5, or pembrolizumab for PD-L1 CPS ≥10, in combination with fluoropyrimidine- and platinum-based chemotherapy is recommended. (EB, B, L, S)
Qualifying statements:
  • For HER2-negative patients with esophageal or GEJ adenocarcinoma, first-line therapy with nivolumab for patients with PD-L1 CPS 1–5, or pembrolizumab for patients with PD-L1 CPS 1–10, in combination with fluoropyrimidine- and platinum-based chemotherapy, may be recommended on a case-by-case basis.
  • For HER2-negative patients with gastric adenocarcinoma and PD-L1 CPS 0 or PD-L1 TPS 0%, first-line therapy with fluoropyrimidine- and platinum-based chemotherapy, without the addition of PD-1 inhibitors, is recommended.
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Recommendation 1.3

For patients with ESCC and PD-L1 CPS ≥10, pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy is recommended. (EB, B, H, S)
Qualifying statement:
  • Data from the primary analysis of CheckMate 648 supports Recommendation 1.3 in patients with ESCC and PD-L1 TPS ≥1%. Additional exploratory analyses from CheckMate 648 found that 91% of patients across three study arms had PD-L1 CPS ≥1, therefore, CPS ≥1 may be used as a threshold for treatment decision-making if TPS is not available.
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Recommendation 1.4

For patients with ESCC, and PD-L1 tumor positive score (TPS) ≥1%, nivolumab plus fluoropyrimidine- and platinum-based chemotherapy, or nivolumab plus ipilimumab are recommended. (EB, B, M, S)
Qualifying statements for Recommendations 1.1 to 1.4:
  • The PD-L1 cut-offs in Recommendations 1.1 to 1.4 are based on subgroup analyses presented in included studies. All possible cut-offs have not been assessed. Therefore, optimal PD-L1 cut-offs are unknown.
  • Several additional studies of immunotherapy with PD-1 inhibitors plus chemotherapy, compared to placebo plus chemotherapy have shown efficacy. However, these therapy options are not currently FDA-approved.
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Recommendation 1.5

For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic adenocarcinoma, trastuzumab plus pembrolizumab is recommended, in combination with fluoropyrimidine- and oxaliplatin-based chemotherapy. (EB, B, L, S)
Qualifying statements:
  • Recommendation 1.5 is applicable irrespective of CPS or TPS levels. However, the Expert Panel notes that PD-L1 CPS was ≥1 in 87% of patients included in the KEYNOTE-811 RCT.
  • HER2 positivity was defined in KEYNOTE-811 as immunohistochemistry (IHC) 3+ or IHC 2+ with positive in situ hybridization (ISH) (details of testing methodology are contained in Literature review and analysis section of the full Guideline).
  • Trastuzumab plus pembrolizumab and chemotherapy is recommended based on an interim analysis showing a response benefit in the first 264 patients enrolled in KEYNOTE-811. We await the analysis of primary outcomes overall survival and progression-free survival.
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Second- or Third-line Therapy

Recommendation 2.1

For patients with advanced gastroesophageal or GEJ adenocarcinoma whose disease has progressed following first-line therapy, ramucirumab plus paclitaxel is recommended. (EB, B, M, S)
Qualifying statement:
  • Although outside the scope of this review, for patients with gastric or GEJ adenocarcinoma, trifluridine and tipiracil may be offered following progression on second-line therapy.
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Recommendation 2.2

For HER2-positive patients with gastric or GEJ adenocarcinoma who have progressed following first-line therapy, trastuzumab deruxtecan is recommended. (EB, B, M, S)
Note: Although the key evidence for this recommendation includes patients who received therapy in the third-line setting, this option is FDA-approved as a second-line and later therapy option.
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Recommendation Grading

Overview

Title

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer

Authoring Organization

Publication Month/Year

January 5, 2023

Document Type

Guideline

Country of Publication

US

Inclusion Criteria

Male, Female, Adult, Older adult

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Treatment

Diseases/Conditions (MeSH)

D000230 - Adenocarcinoma, D000077277 - Esophageal Squamous Cell Carcinoma

Keywords

immunotherapy, HER2, Esophageal cancer, gastric adenocarcinoma, esophageal squamous cell carcinoma, human epidermal growth factor receptor 2

Source Citation

Shah MA, Kennedy EB, Alarcon-Rozas AE, et al. Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline. J Clin Oncol. 2023 January 5. doi: 10.1200/JCO.22.02331