Clinical and molecular outcomes of gastrointestinal malignancies treated with early phase studies: A retrospective single-center experience.

Abstract

e16433 Background: Several clinical and molecular characteristics, including oncogenic alterations, tumor mutation burden (TMB), mismatch repair (MMR) status and the presence of liver metastasis (LM), are associated with responses to immunotherapy (IO). This study aims to evaluate the clinical outcomes of these characteristics among patients with advanced gastrointestinal (GI) cancers treated with novel therapeutics (IO vs. non-IO) in early-phase trials (EPT). Methods: This single center retrospective study was conducted at the Developmental Therapeutics Institute of Northwestern University from 08/2014 to 08/2023. Study specific radiologic evaluations was used. Both progression-free survival (PFS) and overall survival (OS) was assessed. Pts with PFS was ≥ 3 months were characterized as responders, while those with PFS < 3 months as non-responders. Survival curves were generated utilizing the Kaplan-Meier method. To assess differences between responders and non-responders, logistic regression was employed to evaluate the influence of clinical variables on treatment response, with statistical significance set at p ≤ 0.05. Results: Total of 265 pts were evaluable, 11 of these pts enrolled in two different IO studies during this analysis. Median age 65 years (range 55-72), with 52% males. Tumor types included colorectal (49%), pancreatic (43%), and gastroesophageal (7.9%) cancers. 218 (82%) had documented LM, while 47 (18%) had non-LM. Median lines of EPT = 3 (range 1-9). When evaluating efficacy (n = 276), median PFS and OS was 2.1 (range 1.6-5.0) months and 6.0 (range 3-11) months respectively, with a 42% PFS rate of ≥ 3 months in all patients. Non-IO therapy correlated with higher PFS 3.0 (range 1.6-5.5)compared to IO therapy 1.8 (range 1.5-3.9) (p = 0.00078) without OS differences (p = 0.15). Stratification by LM significantly impacted PFS (p = 0.0016) and OS (p = 0.0012) in the non-IO cohort but did not impact in the IO cohort. Next-generation sequencing of 165 patients found that a TMB of ≥ 10 (12%) and deficient MMR (1.4%) did not correlate with IO response. Key driver mutations like TP53, KRAS, and APC were similarly expressed in both LM and non-LM patients. Notably, KRAS mutations were linked to lower odds of response to IO therapy (odds ratio: 3.19, p = 0.023). Conclusions: In contrast to prior studies, our data do not indicate a significant association between LM and survival outcomes with IO-based EPT. This discrepancy maybe related to heterogeneity of IO regimens and limited sample size. Role of KRAS mutations as a negative predictor of response to IO requires further validation. Given the limited effectiveness of non-IO EPT in patients with LM, it is suggested that treatment resistance in LM is not limited only to IO therapies. Patients with and without LM show similar molecular characteristics, indicating that resistance may arise from the unique TME in the liver.