ASCO Guidelines Shine Light on Treatments for Gastroesophageal Cancer

The American Society of Clinical Oncology (ASCO) has released new guidelines providing recommendations for the optimal treatment of patients with advanced gastroesophageal cancer following a systemic review of 18 randomized controlled trials by an expert panel.

Phase 2 and 3 trial data spanning January 1, 2010, to March 4, 2022, informed the recommendations. The panel noted that implementation of these guidelines is dependent on PD-L1 testing, which may not be available universally.

The updated first-line therapy recommendations encompassed 5 subgroups of patients with advanced gastroesophageal cancers and addressed 2 clinical questions:

• Is immunotherapy or targeted therapy in combination with chemotherapy recommended as first-line treatment for advanced gastroesophageal adenocarcinoma or squamous cell carcinoma for subgroups of patients with HER2-negative disease with PD-L1 expression defined by tumor proportion score (TPS) or combined positive score (CPS) at cutoff levels of ≥1, ≥5, or ≥10 or patients with HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma?
• Is immunotherapy or targeted therapy recommended as second- or third-line treatment for advanced gastroesophageal adenocarcinoma?

There were approximately 769,000 deaths due to gastric cancer in 2020 and the GEJ is the fastest growing cancer site in Western populations. Either TPS or CPS can be used to measure PD-L1 expression and inform treatment decisions; however, TPS is the ratio of PD-L1 expressing cells to all viable tumor cells, and CPS also includes the number of PD-L1 positive lymphocytes and macrophages, deeming it a more prognostic biomarker in gastric and GEJ cancer for immunotherapy efficacy.

The panel recommended a shared decision-making approach and participation in clinicals trials for all patients, as it anticipates the expansion of treatments for gastroesophageal cancer in the future. Targeted therapies have demonstrated efficacy in subgroups of patients with PD-L1 and/or HER2 expression. Immunotherapies are also a viable treatment option for patients with gastroesophageal cancer.

First-Line Treatment Recommendations:

Patients with HER2-negative gastric adenocarcinoma and a PD-L1 CPS of 5 or greater should receive nivolumab (Opdivo) in combination with fluoropyrimidine- and platinum-based chemotherapy. However, patients with a CPS of 1 to 5 may be considered on a case-to-case basis for the combination regimen and those with a CPS of 0 should only receive fluoropyrimidine- and platinum-based chemotherapy.

Based on PD-L1 CPS, pembrolizumab (Keytruda) and nivolumab are the recommended options for patients with HER2-negative esophageal or GEJ adenocarcinomas in combination with fluoropyrimidine- and platinum-based chemotherapy. Patients with a CPS of 5 or greater should receive nivolumab; those with a score 10 or greater are candidates for pembrolizumab. Additionally, patients with gastric adenocarcinoma and a PD-L1 CPS of 0 or PD-L1 TPS of 0%, should solely receive fluoropyrimidine- and platinum-based chemotherapy.

Pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy is recommended for patients with HER2-negative esophageal squamous cell carcinoma (ESCC) and a PD-L1 CPS of 10 or greater. Patients with HER2-negative ESCC and a PD-L1 TPS of either at least 1% or a CPS of at least 1, should receive either nivolumab plus fluoropyrimidine- and platinum-based chemotherapy or nivolumab plus ipilimumab (Yervoy). It was noted that immunotherapies with chemotherapies plus PD-L1 inhibitors have demonstrated efficacy in many studies but are not yet FDA approved.

The final first-line treatment recommendation for patients with HER2-positive gastric or GEJ previously untreated, unresectable, or metastatic adenocarcinoma was trastuzumab (Herceptin) plus pembrolizumab in combination with fluoropyrimidine- and oxaliplatin-based chemotherapy irrespective of CPS or TPS.

Second- or Third-Line Treatment Recommendations:

Under the new guidelines, patients with advanced gastroesophageal or GEJ adenocarcinoma with disease progression after first-line therapy should receive ramucirumab (Cyramza) plus paclitaxel. Investigators also stated that patients with gastroesophageal or GEJ adenocarcinoma may be treated with trifluridine and tipiracil after progression on second-line therapy; however they noted that this was outside of the scope of the review.

It was advised that after progression on first-line therapy patients with HER2-positive disease with gastric or GEJ adenocarcinoma receive fam-trastuzumab deruxtecan-nxki (Enhertu). The agent is approved for patients who were treated in the third-line setting as well as second line.

A draft of the recommendations was made available for comment from the public from August 8, 2022, to August 22, 2022. After a respondent posed the question of which assay should be used to detect PD-L1 expression, the discussion portion of the guidelines was modified to specify the 28-8 pharmDx or 22C pharmDx tests. Additionally, 66% of respondents agreed or agreed with slight modifications to the recommendations and 33% of the respondents disagreed. The ASCO panel also included a literature search identifying the 519 studies that informed the guidelines.

Reference

Shah MA, Kennedy EB, Alarcon-Rozas AE, et al. Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO guideline. J Clin Oncol. Published online January 5, 2023. doi:10.1200/JCO.22.02331