TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study

Abstract

In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

Immunotherapy-Based Neoadjuvant Treatment of Advanced Microsatellite Instability–High Gastric Cancer: A Case Series

“…Data remain nascent, such as from the NEONIPIGA trial, 38 in which relatively high pathologic complete response rates to ICIs alone in MSI-H disease raises the question of whether surgery can be avoided. Newer trials, such as INFINITY, 39 which is examining the ICIs durvalumab and tremelimumab without chemotherapy initially as a neoadjuvant approach in MSI-H GC, will attempt to validate in a later cohort whether this approach can support nonoperative management. However, these studies remain ongoing, and there are currently limited prospective data from which we are able to validate the omission of surgery completely for these patients.…”

Dual immune checkpoint blockade in gastroesophageal tumors: never say never

“…As observed in NEONIPIGA trial, it is a matter of debate whether patients with complete response after neoadjuvant treatment would still need a surgical resection of the tumor. INFINITY is an ongoing phase II, multicenter, single-arm, multicohort trial investigating the activity and safety of treme-limumab+durvalumab as neoadjuvant (cohort 1) or definitive (cohort 2) treatment for centrally determined MSI-high/dMMR/EBV-negative, resectable gastroesophageal tumors [24]. Adjuvant treatment should be applied based on standard follow-up.…”

Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers

“…The results indicate that pembrolizumab or pembrolizumab plus chemotherapy provided durable antitumor activity compared to chemotherapy alone in patients with an MSI gastric junction or gastroesophageal cancer. Other clinical trials have suggested drug combinations, such as durvalumab and tremelimumab or nivolumab and ipilimumab in phase 2, for the treatment of advanced MSI GC [ 104 , 105 , 106 ] ( Table 3 ). The comparative analysis between these methods showed some discrepancies, particularly as some dMMR-IHC cases were MSS by PCR (ranging from 1% to 38%) [ 51 , 107 ], while pMMR-IHC cases were MSI by molecular analysis (ranging from 1% to 7,4%) [ 52 , 108 , 109 ].…”