At the 2023 ASCO Gastrointestinal Symposium, Filippo Pietrantonio, MD, Fondazione IRCCS—National Cancer Institute, Milan, Italy, shares results from the INFINITY trial. This phase 2 study evaluated the use of a neoadjuvant combination of immune checkpoint inhibitors and tremelimumab plus durvalumab for patients with resectable microsatellite instability-high gastric/gastroesophageal junction adenocarcinoma.

Dr Pietrantonio noted that while this was a small study with a need for larger follow-up, chemotherapy-free immunotherapy combinations such as this one will soon become a standard of care for this patient population.

Transcript:

Hi everyone, my name is Filippo Pietrantonio. I'm a medical oncologist at the National Cancer Institute of Milan. At the 2023 ASCO Gastrointestinal Cancers Symposium, the INFINITY trial cohort 1 was presented. This study was sponsored by the Gruppo Oncologico Del Nord Ovest (GONO) Foundation in Italy.

Some background: microsatellite instability (MSI) is associated with better survival and potential lack of benefit from chemotherapy in patients with resectable gastroesophageal junction cancer, and it is one of the strongest predictors of the efficacy of immunotherapy. In early-stage disease, the activity is even higher, and the immune checkpoint inhibitors may allow the omission of chemotherapy, radiotherapy, or even surgery. And finally, a single dose of tremelimumab, an anti-CTLA4 agent, plus the anti-PD-L1 agent, durvalumab, may induce t-cell expansion, and is approved for the treatment of patients with hepatocellular carcinoma.

The INFINITY trial enrolled the patients with MSI-high and deficient mismatch repair (DMMR) resectable gastroesophageal junction cancer. And patients were treated with the STRIDE regimen: high-dose tremelimumab 300 mg plus durvalumab, for 3 doses every 4 weeks, then standard surgery, plus standard follow-up. The results of cohort 1 have been evaluated by an international independent data monitoring committee. Now, recruitment in cohort 2 has started to evaluate the same regimen as a non-operative management strategy.

The primary endpoints of cohort 1 was pathological complete response associated with negative minimal residual disease in ctDNA before surgery. Secondary end points were disease-free and overall survival, surgical safety, safety of the treatment, quality of life, and translational analysis. There were 18 patients enrolled, so this was a small proof-of-concept study, 1 patient withdrew informed consent after 1 cycle, and 2 patients refused surgery because of a complete clinical response.

Among 15 patients evaluable for the primary end point, just 1 had systemic disease progression and 14 were radically resected. Regarding the baseline characteristics of these patients, the median age was very high, 71 years old, consistent with the microsatellite instability status, and 40% of them had clinical stage T4 tumors. We evaluated the resected patients, most of them had pathological downstaging. Only 2 non-responders were reported, and 1 of them had heterogeneous mismatch repair status after surgery. This highlights the importance of adequate initial sampling in these patients. Among all the evaluable patients, the PCR rate was 60%, so quite encouraging. And the rate of major to complete pathological response was 80%.

Regarding survival, as we said, 2 patients had systemic disease progression and an additional 3 patients unfortunately died, without disease progression, because of late post-operative complications — please remember that the median age of these patients was very high — and 1 from a second primary brain cancer. The gastric cancer-specific progression-free survival and overall survival were quite encouraging despite the limited sample size. No unexpected immune-related adverse events occurred. Grade 3 or more toxicity occurred at very low frequency and did not impair the feasibility of surgery. Also, we analyzed the quality of life, and the global quality of life was maintained during the new adjuvant phase.

Regarding subgroup analysis, it is important to note that a significant association was found for PCR and T-stage, but not for end-stage. In particular, the PCR rate was very low in the T4 subgroup. And finally, in translational data, a numerical association was found for PCR and baseline tumor mutational burden, but not for PD-L1 CPS.

As a summary, the neoadjuvant treatment with the tremelimumab 300 mg plus durvalumab was safe and had promising eradicating activity in patients with MSI-high and DMMR resectable, gastroesophageal junction cancer. Despite the limited sample size and the need of larger studies, these chemo-free immunotherapy combinations will represent soon a standard of care in this small molecular subgroup. However, the optimal combination, treatment duration, and the goal of treatment, whether it is adjuvant or organ preservation, should be further investigated by future studies. And, in fact, the enrollment in Cohort 2 of the INFINITY trial is ongoing after the ADMC evaluation and protocol amendment to exclude T4 tumors from non-operative management.

Thank you so much for your attention and I would like to thank the GONO Foundation, which is the sponsor of the trial and has allowed us to do many academic studies in Italy. Thank you so much.

Source:

Pietrantonio F, Raimondi A, Lonardi S, 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). Presented at 2023 ASCO Gastrointestinal Symposium; January 19-21, 2023; San Francisco, California. Abstract 358