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.

Alessandra Raimondi,Federica Palermo,Elena Ongaro,Filippo Pietrantonio,Michele Prisciandaro,Giuseppe Aprile,Emiliano Tamburini,Chiara Cremolini,Antonia Strippoli,Rossana Berardi,Francesca Pucci,Vincenzo Mazzaferro,Massimo Aglietta,Lorenzo Antonuzzo,Nicola Silvestris,Alberto Zaniboni,Lorenzo Fornaro,Roberto Murialdo,Maria Di Bartolomeo,Giovanni De Manzoni,Sara Lonardi,Margherita Ratti,Francesco Iachetta,Valeria Smiroldo,Carlo Sposito,Ferdinando De Vita,Andrea Spallanzani,Cristina Granetto,Stefano Tamberi,Giovanni Gerardo Cardellino ,Giovanni Luca Frassineti ,Massimo Di Maïo

doi:10.3390/cancers13112839

Abstract

Simple SummaryThe status of microsatellite instability (MSI-H) in gastric or gastroesophageal junction cancer (GC/GEJC) patients eligible for radical surgery proved to be prognostic for an improved survival outcome and predictive for poor/no benefit from the combination of adjuvant/peri-operative chemotherapy. MSI-H tumors display a high sensitivity to immunotherapy and exploratory studies showed that a pre-operative treatment with immune-checkpoint inhibitors may achieve elevated rates of pathological complete responses. The ongoing proof-of-concept INFINITY study is aimed at investigating the role of the combo-immunotherapy durvalumab plus tremelimumab as a neoadjuvant or potentially definitive treatment (avoiding surgery in case of complete clinical response) for MSI-H resectable GC/GEJC patients.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.

Highlights

Gastric cancer (GC) and gastroesophageal junction cancer (GEJC) globally represent the fourth most common cancer and the second leading cause of cancer-related death [1].Despite the evolution of the disease management thanks to the development of multimodality treatment strategies, gastric or gastroesophageal junction cancer (GC/GEJC) remains one of the most lethal malignancies with unsatisfactory long-term survival outcomes [2].The cornerstone of potentially curative treatment remains surgery, total/subtotal gastrectomy with lymphadenectomy
The primary objective of the study is to assess the activity of the combination immunotherapy with tremelimumab plus durvalumab as a neoadjuvant or definitive treatment of resectable Microsatellite instability (MSI)-H GC/GEJC
The treatment decision-making for resectable GC/GEJC is currently based upon the clinical and pathological staging, in absence of validated biomarkers potentially able to select patients eligible for the combination with adjuvant/peri-operative chemotherapy or surgery alone [19]

Summary

Introduction

Gastric cancer (GC) and gastroesophageal junction cancer (GEJC) globally represent the fourth most common cancer and the second leading cause of cancer-related death [1].Despite the evolution of the disease management thanks to the development of multimodality treatment strategies, GC/GEJC remains one of the most lethal malignancies with unsatisfactory long-term survival outcomes [2].The cornerstone of potentially curative treatment remains surgery, total/subtotal gastrectomy with lymphadenectomy. The research focused on the integration of systemic treatments for localized or locally advanced disease, in order to improve the survival outcome of patients and/or to increase the rate of radical surgical resections [3,4,5,6,7]. Adjuvant chemotherapy in a GC setting was primarily supported by the ACTS-GC [6] and CLASSIC [5] studies, and the GASTRIC group metaanalysis [7]. Both chemotherapy approaches are evidence-based and guideline-endorsed, the adjuvant schedule is preferred in Asian countries and the perioperative one outside of Asia. Disease relapses still occur in a substantial number of patients, who eventually die for their disease and, on the other side, some patients are cured by surgery alone and do not require additional therapy, they receive potentially toxic treatments without a significant benefit [8,9]

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