Outcomes of patients with refractory upper GI cancers enrolled in phase I trials: a 10-year analysis from the Sarah Cannon Research Institute UK Drug Development Unit.

Abstract

Background: Patients with unresectable upper gastrointestinal (UGI) cancers have limited treatment options and poor prognosis. Although phase I trials provide access to novel therapies, their benefits in this population are unclear.

Objectives: We aimed to assess efficacy and survival outcomes of patients with refractory UGI cancers within phase I trials.

Design: We conducted a retrospective pooled analysis of phase I trials enrolling patients with advanced UGI cancers who received at least one dose of the study drug at SCRI UK between 2011 and 2023.

Methods: Efficacy and survival outcomes, including objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS), were assessed. Analyses were conducted for the entire cohort and stratified by trial agent class, molecularly matched therapy allocation and receipt of the recommended phase II dose (RP2D). Patients participating in multiple trials were analysed separately for each study.

Results: From 1796 screened patients, 124 with UGI cancers were included in 37 phase I trials. Most were male (75%), with liver or peritoneal metastases (73%), treated with a median of 2 prior therapy lines. Of these, 60% received immunotherapy, 30% small molecules and 10% antibody-drug conjugates. Molecularly matched therapy was given to 22% and 86% received treatment at RP2D. In response-evaluable patients, ORR was 15%, CBR 40%, DCR 86% and median OS was 9.7 months. Treatment at RP2D was significantly associated with higher CBR (odds ratio 4.75, p = 0.04) and prolonged PFS (p = 0.04). Depth of response and treatment at RP2D were independent prognostic factors.

Conclusions: Participation in phase I trials offers benefits in refractory upper gastrointestinal cancers with compelling results in late-line settings and potential early access to new therapies.