Immune checkpoint inhibitors may be associated with high and durable response rates in patients with deficient mismatch repair or microsatellite instability–high gastroesophageal adenocarcinoma. More than half of evaluable patients with locoregional disease achieved either clinical complete response or pathological complete response, and no complete responders experienced recurrence during follow-up.
Researchers assigned 1,638 patients with gastroesophageal adenocarcinoma to undergo microsatellite instability (MSI) testing, 5% (n = 83) of whom had deficient mismatch repair (dMMR) tumors. They then evaluated treatment patterns and outcomes following Immune checkpoint inhibitor (ICI) therapy with either nivolumab plus ipilimumab or pembrolizumab in both metastatic and locoregional disease.
The primary outcomes included best objective response rates in metastatic disease and clinical or pathologic complete response rates in locoregional disease. Among the 26 evaluable patients with metastatic disease treated with ICIs, 62% (n = 16) of them achieved an objective response. Among the 23 evaluable patients with locoregional disease treated with ICIs, 52% (n = 12) of them achieved either clinical or pathologic complete response . Nine patients who achieved clinical complete response transitioned to active surveillance.
Responses also appeared durable. The researchers reported that no patients who achieved clinical or pathologic complete response experienced recurrence or mortality during a median follow-up of 26 months.
The researchers observed differences in response timing between the treatment regimens. The patients treated with nivolumab plus ipilimumab achieved complete response following two to four cycles, whereas those treated with pembrolizumab generally required six to 12 cycles. However, the researchers noted that differing treatment schedules limited direct comparisons between the regimens.
Patients with dMMR tumors also demonstrated better overall survival compared with those with proficient mismatch repair tumors, regardless of whether they underwent curative-intent surgery. Three-year overall survival rates among the patients with dMMR tumors who underwent surgery were 85% vs. 72% for proficient mismatch repair tumors. Among those who did not undergo surgery, the 3-year overall survival rates were 69% vs. 32%, respectively.
In an invited commentary accompanying the study, Michael K. Srienc, MD, and Timothy R. Donahue, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, cautioned that nearly half of the patients with locoregional disease did not achieve complete response following immunotherapy. They wrote that "dMMR/MSI-[high] status alone may be insufficient to reliably distinguish responders from nonresponders in [gastroesophageal adenocarcinoma], and more importantly, unable to identify patients who can be safely managed without surgery after ICI treatment."
The researchers acknowledged several limitations, including the retrospective single-center design, incomplete follow-up in some patients, and nonstandardized treatment selection. Response assessments were also performed retrospectively without blinded central review.
The findings suggested that ICI therapy may support nonoperative management strategies in selected patients with dMMR/MSI-high gastroesophageal adenocarcinoma, although prospective studies will be needed to determine which patients can safely defer surgery, according to lead study author Jun Okui, MD, MPH, PhD, of the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, and colleagues.
The study authors reported no conflicts of interest. Dr. Donahue reported serving as a shareholder and board director at Trethera Corporation. No other conflicts of interest were reported.
Source: JAMA Surgery, Editorial
