TOPLINE:

In a pooled data analysis of patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) resectable gastroesophageal adenocarcinoma, neoadjuvant CTLA‑4/PD‑(L)1 blockade was associated with higher pathologic complete response (pCR) and major pathologic response (MPR) than the fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen but did not improve event‑free survival (EFS) or overall survival (OS) vs surgery alone.

METHODOLOGY:

• Patients with dMMR/MSI-H resectable gastroesophageal adenocarcinoma have a relatively favorable prognosis and limited benefit from an older chemotherapy regimen. Recent trials showed that neoadjuvant CTLA‑4/PD‑(L)1 blockade produces high pathologic responses, but its impact on long‑term outcomes compared with FLOT or surgery alone remains uncertain.
• Researchers conducted an individual patient data pooled analysis of seven studies (six multicenter trials and one retrospective cohort study) and analyzed 197 patients (median age, 66 years) with dMMR/MSI‑H resectable gastroesophageal adenocarcinoma. Of them, 49 received immune checkpoint inhibitors (ICIs), 27 received FLOT, 33 underwent surgery alone, and 88 received surgery plus older chemotherapy regimens.
• Primary endpoints were pCR, defined as the absence of viable tumor, and MPR in patients who underwent surgery; secondary endpoints were EFS and OS in the full cohort.
• Researchers evaluated patients who underwent surgery after ICIs or FLOT (n = 69) comparing pathologic response rates and nodal status between groups.
• The median follow-up duration was 30.7 months for ICIs, 30.1 months for FLOT, 59.7 months for older chemotherapy regimens plus surgery, and 62 months for surgery alone.

TAKEAWAY:

• Among the 69 patients who underwent surgery, ICIs demonstrated significantly higher pathologic response than FLOT (pCR: 61.9% vs 3.7%; odds ratio [OR], 54.8; P = .002; MPR: 78.6% vs 10%; OR, 39.3; P < .001).
• No significant differences in EFS or OS were observed between patients who received ICIs and surgery alone (36-month EFS and OS were 70.4% vs 80.6% and 72.7% vs 90.4%). In adjusted Cox models, ICIs vs surgery alone did not significantly change EFS (hazard ratio [HR], 1.39; P = .52) or OS (HR, 1.97; P = .38).
• Regarding pathologic downstaging after neoadjuvant treatment in resected patients, 85.7% vs 63.0% had ypN0 status after ICIs vs FLOT (OR, 4.2; P = .015). None of the patients who underwent resection after ICIs vs 29.6% after FLOT had ypT4 status (P < .001).
• Residual nodal disease (ypN+) was strongly associated with worse OS and progression-free survival (PFS) than ypN0 status (OS: HR, 4.85; P = .0018; PFS: HR, 7.48; P < .0001). ypT4 status was associated with worse PFS (HR, 7.00; P < .0001) and trended toward worse OS.

IN PRACTICE:

“Our pooled analysis reinforced the high activity in terms of pathologic response of ICIs in resectable dMMR/MSI-H [gastroesophageal adenocarcinoma], though showing comparable survival outcomes with surgery alone” the authors wrote, concluding that “future trials investigating organ-sparing or nonoperative strategies in patients with complete clinical response to ICIs are warranted to reduce surgical morbidity and mortality and to improve the quality of life of patients.”

SOURCE:

This study, led by Alessandra Raimondi, MD, Istituto Nazionale Tumori IRCCS in Milan, Italy, was published online in Journal of Clinical Oncology.

LIMITATIONS:

The analysis had several limitations, including heterogeneity in trial design, historical periods, regions or countries, and follow-up duration, which was shorter in studies with ICIs and FLOT. While follow-up was mature at over 30 months in all groups, variations in treatment protocols and relatively small sample size across different trials could have affected generalizability of the results.

DISCLOSURES:

This study was supported and sponsored by Gruppo Oncologico del Nord Ovest as an academic study. Several authors reported receiving honoraria or research funding and having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.