Neoadjuvant immunotherapy is safe and efficacious in a phase 2 gastric cancer trial

Neoadjuvant tremelimumab plus durvalumab displayed encouraging activity and a favourable safety profile in patients with microsatellite instability-high (MSI-H), resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC) in the phase 2 INFINITY trial

In patients with GAC/GEJAC, MSI-H status has been linked to improved survival outcomes and a reduced benefit from chemotherapy [1]. On the other hand, immunotherapy is effective in MSI-H tumours [2]. Therefore, the combination of CTLA-4 inhibition and PD-L1 inhibition may result in the possibility of omitting chemotherapy or surgery in these patients.

The multicentre, single-arm, phase 2 INFINITY trial (NCT04817826) assessed the efficacy and safety of tremelimumab plus durvalumab as neoadjuvant therapy in a cohort of 18 patients with MSI-H, mismatch repair deficient (dMMR), and EBV-negative resectable GAC/GEJAC [3]. In a second cohort, this therapy will be assessed as a definitive treatment for patients with this indication. In the neoadjuvant cohort, patients received a single dose of 300 mg tremelimumab and 1,500 mg durvalumab, every 4 weeks. The primary endpoint was the pathological complete response (pCR) with negative ctDNA after 12 weeks of treatment. Dr Filippo Pietrantonio (Fondazione IRCCS Istituto Nazionale dei Tumori, Italy) presented the findings [3].

In total, 9 out of 15 evaluable patients achieved a pCR with negative ctDNA status (60%) prior to surgery. The major-complete pathological response rate (<10% viable cells) was 80%. According to Dr Pietrantonio, the global quality-of-life was preserved during the neoadjuvant treatment.

Pre-operative treatment with tremelimumab and durvalumab was generally safe. In 3 patients, grade ≥3 immune-related adverse events (AEs) occurred; hepatitis, colitis, and pneumonitis, one case each. The most common grade 1 or 2 AEs were pruritis (22%), thyroiditis (22%), hepatitis (17%), and skin rash (17%).

The combination of tremelimumab and durvalumab appeared to be safe and displayed encouraging activity in the current phase 2 trial. “Although larger studies are needed, chemotherapy-free, immune checkpoint inhibitor-based strategies will represent a standard-of-care in the molecular subgroup of MSI-H dMMR tumours in the foreseeable future,” argued Dr Pietrantonio. “Of course, optimal combinations and therapy duration should be further investigated.” This data is important for potential non-operative management as in locally advanced rectal cancer.

1. Pietrantonio F, et al. JCO. 2019;37(35):3392–3400.
2. Leone AG, et al. ESMO Open. 2022;7(1):100380.
3. Pietrantonio F, et al. INFINITY: A multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). Abstract 358, ASCO GI 2023, 19–21 January, San Francisco, CA, USA.

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Posted on 17 March 202321 May 2024