Individual patient data (IPD) pooled analysis on the optimal therapeutic management of patients with microsatellite instability-high (MSI) resectable gastroesophageal adenocarcinoma (GEA).
Authors: Raimondi Alessandra , Tine' Gabriele , Tougeron David , Lonardi Sara , Ricagno Gianmarco , Cardellino Giovanni Gerardo , Nappo Floriana , De Vita Ferdinando , Nankivell Matthew Guy , Cunningham David , Lee Jeeyun , Kang Won Ki , Cheong Jae-Ho , Choi Yoon Young , Polymeropoulos Alessio , Pircher Chiara Carlotta , Miceli Rosalba , Piessen Guillaume , Andre Thierry , Pietrantonio Filippo 
Published: January 2025

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Background:
Patients with resectable MSI/dMMR GEA showed improved survival and modest if any benefit from chemotherapy. Preoperative treatment with immune checkpoint inhibition (ICI) showed high rate of major-complete pathologic response in single arm trials possibly allowing the design of chemotherapy/surgery-free approaches.
Methods:
This was a multinational IPD analysis including patients with resectable GEA with MSI/dMMR status enrolled in INFINITY and NEONIPIGA phase II trials, with dual CTLA-4/PD-(L)1 ICI followed by surgery +/- adjuvant ICI; PROSECCO retrospective study, with perioperative FLOT chemotherapy and surgery, and the dataset of our previous IPD analysis on MAGIC, CLASSIC, ARTIST and ITACA-S randomized trials of patients treated with surgery alone or plus older perioperative/adjuvant chemo(radio)therapy regimen. Primary endpoint was the evaluation of rates of pathologic complete response (pCR) defined as TRG1a Becker and major-complete pathologic response (pCR/MPR) defined as TRG1a/b Becker according to preoperative treatment schedule in patients who underwent surgery. Univariable and multivariable analyses were conducted using a random effects logistic model adjusted with propensity score. Secondary endpoints were event-free survival (EFS) and overall survival (OS) according to the therapeutic strategy in the overall study population. Multivariable mixed-effects Cox models weighted with propensity score were performed.
Results:
The IPD included 197 patients. Of these, 49 received ICI +/- surgery, 27 FLOT chemotherapy plus surgery, 33 surgery alone and 88 older chemo(radio)therapy regimens plus surgery. In the 69 patients resected after neoadjuvant ICI or FLOT standard of care treatment, ICI demonstrated a higher rate of pathologic response compared to chemotherapy (pCR 61.9% vs 3.7%, OR 54.8 p=0.002; pCR/MPR 78.6% vs 10%, OR 39.3 p<0.001). In ITT population, no significant difference in OS and EFS was shown in patients treated with ICI, FLOT plus surgery, old chemo(radio)therapy plus surgery or surgery alone.
Conclusions:
In resectable MSI/dMMR GEA, upfront ICI showed comparable survival outcomes to surgery alone, with limitations of study design and sample size. The impact on survival of ICI versus surgery alone should be investigated prospectively to avoid overtreatment or identify specific risk categories with benefit. The high rate of major-complete pathologic response may allow to study or perform organ sparing surgery procedures or non-operative management to reduce surgical morbidity/mortality and improve quality of life.

OS
EFS

HR
2.5-97.5% CI
p
HR
2.5-97.5% CI
p

Ref: Surgery only
-
-
-
-
-
-

Chemo+surgery
1.16
0.27-4.98
0.84
1.10
0.39-3.07
0.85

FLOT+surgery
1.10
0.19-6.22
0.92
2.38
0.90-6.27
0.08

ICI +/- surgery
1.97
0.43-8.96
0.38
1.39
0.51-3.77
0.52