Neoadjuvant Tremelimumab/Durvalumab Combination Exhibits Antitumor Activity in G/GEJ Cancer
Neoadjuvant immunotherapy shows antitumor activity in mismatch repair deficient/MSI gastric/gastroesophageal junction adenocarcinoma.
Microscopic image of gastric tumor cells - Generated with Google Gemini AI
Findings of the phase 2 INFINITY trial (NCT04817826) indicate that a chemotherapy-free regimen of tremelimumab (Imjudo) plus durvalumab (Imfinzi; T300/D) exhibited promising antitumor activity in patients with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H), resectable gastric/gastroesophageal junction adenocarcinoma.1 The study, published in Annals of Oncology, explored the activity and safety of T300/D in both neoadjuvant and definitive treatment settings, and presented results from 2 distinct cohorts.
Both cohorts received tremelimumab at a single dose of 300 mg on day 1 and durvalumab at 1500 mg every 4 weeks for 3 cycles.
Neoadjuvant Treatment
At the data cutoff of April 8, 2024, and a median follow-up of 28.1 months, 9 (60%) patients in cohort 1 (n = 18) achieved partial complete response (pCR) and 12 (80%) achieved major pathologic response (MPR)-pCR. Two patients had progressive disease.
Investigators reported that median progression-free survival (PFS), overall survival (OS), and gastric cancer (GC)-specific PFS and OS, were not reached. At 24 months, PFS, OS, GS-specific PFS/OS rates were 66.7%, 73.3%, 84.8%, and 91.7%, respectively.
For cohort 1, the primary end point was the activity of T300/D as a neoadjuvant treatment, measured by pCR. Secondary end points included PFS and OS.
Definitive Treatment
In cohort 2 (n = 18), 17 patients were determined to be evaluable. Thirteen (76%) patients had clinical CR (cCR) and started non-operative management. Conversely, 4 (24%) patients did not achieve cCR, and of these, 3 patients had a positive and 1 patient had a negative liquid biopsy.
At the data cutoff of July 23, 2024 and median follow up of 11.5 months, the median PFS and OS were not reached; the 12-month PFS, OS, and gastrectomy-free survival (GFS) rates were 93.8% (95% CI, 83.0%-100%), 100% (95% CI, 100%-100%), and 64.2% (95% CI, 44.4%-92.8%), respectively, in the evaluable population, and 93.8%, 100%, and 62.1%, respectively, in the intention-to-treat population.
The primary end point of cohort 2 was the rate of radiological, metabolic, pathological, and molecular cCR levels at 2 years. Secondary end points were PFS, OS, metastases-free survival, GFS—defined as the time from the enrollment in the study to the occurrence of gastrectomy or death from any cause—safety, and quality of life.
Demographics and Safety
The median age of patients at baseline was 71.5 years (range, 65-80) in cohort 1 and 74.0 years (range, 66.5-77) in cohort 2. The majority of patients were male with 67% in cohort 1 and 56% in cohort 2. Most patients had tumors in stage T3 (56% in cohort 1 and 61% in cohort 2).
Regarding safety, in cohort 1, 72% of patients experienced any grade adverse events (AEs). The most reported were pruritus, skin rash, and hypothyroidism/hyperthyroidism. Only 17% of patients experienced grade 3 or higher immune-related AEs.
In the safety population of cohort 2, 72% experienced any grade AEs, with the most common being colitis, thyroiditis, pruritus, and skin rash. A total of 17% had grade 3 or higher immune related AEs that included colitis, gamma-glutamyl transferase elevation, and thyroiditis. All AEs were resolved with treatment as per protocol.
Clinical Implications
Although the use of neoadjuvant immunotherapy has benefit, its clinical usefulness compared with surgery alone remains a subject of ongoing investigation. For patients with dMMR/MSI-H tumors, surgery alone has demonstrated better survival outcomes than in patients with proficient mismatch repair/microsatellite stability tumors. However, investigators noted that approximately 25% of patients experience disease relapse after surgery, underscoring the need for improved treatment strategies to reduce mortality.
The authors wrote in their study that the pCR and MPR rates of 60% and 80%, respectively, were in line with those from the NEONIPIGIA study (NCT04006262). This study evaluated preoperative ipilimumab (Yervoy) plus nivolumab (Opdivo) for 3 months and postoperative nivolumab for 9 months resulting in a 59% pCR and 73% MPR rate.2
The INFINITY trial highlights the potential of chemotherapy-free immunotherapy regimens in improving outcomes for patients with dMMR/MSI-H resectable gastric/gastroesophageal junction adenocarcinoma.
