Immune checkpoint inhibitors in combination with chemotherapy are part of standard treatment for patients with advanced gastroesophageal adenocarcinoma. However, not all patients benefit from immunotherapy addition. Programmed death-ligand 1 (PD-L1) expression has emerged as a useful, yet imperfect, biomarker for identifying patients who are most likely to benefit from the addition of immunotherapy. There is a need to better identify patients with higher chances of responding to these therapies, as well as a need to augment the activity that we are seeing with current approaches. Tumor mutational burden (TMB) has been previously identified as a predictive biomarker of response to immunotherapy. It is not widely used in clinical practice when treating patients with upper gastrointestinal cancers though, and it has not been extensively evaluated in this disease.
The study by Lee and colleagues evaluated the association between TMB and pembrolizumab response in patients treated in the phase 3 KEYNOTE-62 study. This was a prespecified exploratory analysis, which included 306 of 763 patients, based on TMB data availability. Although there was association between high TMB (cut-off defined as 10 mut/Mb), the benefit from pembrolizumab was most pronounced in patients with microsatellite-unstable tumors. When the analysis was limited to microsatellite-stable tumors with high TMB, the signal was attenuated and was only detected when immunotherapy was combined with chemotherapy.
Ultimately, although TMB is a predictive biomarker of response to immunotherapy, it is unlikely to significantly alter our approach to treatment of upper gastrointestinal cancers, especially when PD-L1 testing and microsatellite testing are more readily available and do not require more time- and resource-consuming next-generation sequencing when selecting first-line treatments.
Perioperative chemotherapy plays a critical role in the management of patients with early-stage gastric cancer. In the United States, perioperative FLOT (5-fluorouracil, oxaliplatin, and docetaxel) chemotherapy is the standard approach to this disease, with four cycles administered before and four cycles administered after resection.
In Korea, adjuvant chemotherapy is typically used, with 1 year of S-1 chemotherapy or 6 months of CAPOX (capecitabine/oxaliplatin) chemotherapy used most frequently. Kim and colleagues analyzed whether a shorter duration of chemotherapy (either S-1 or CAPOX) had similar outcomes. In a retrospective analysis of 20,552 patients, which included 13,614 patients who received S-1 and 6938 patients who received CAPOX, overall survival was worse in those patients who received a shorter duration of adjuvant treatment. Although this study is not directly applicable to how we approach treatment of early-stage gastric cancer in the United States, it does suggest that any modification in the duration of perioperative chemotherapy should be evaluated in prospective clinical trials, similarly to recent investigations regarding the duration on adjuvant chemotherapy in colon cancer.