The influence of timing: A retrospective analysis of short-course TKI induction and survival outcomes in refractory MSS colorectal cancer.

Abstract

e15573 Background: The concurrent use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has shown limited efficacy in microsatellite stable (MSS) colorectal cancer (CRC). This limitation likely arises from an unprimed, "cold" tumor microenvironment (TME). Recent evidence suggests that TKI-induced vascular normalization creates a transient “window of opportunity” for immune activation. We hypothesized that a sequential approach, TKI induction followed by ICIs, might outperform concurrent administration by effectively remodeling the TME. Methods: In this retrospective cohort study, 78 patients with refractory advanced CRC treated at Harbin Medical University Cancer Hospital (Jan 2019–Apr 2024) were enrolled. Patients were categorized into a Sequential Group (n = 33, initial TKI induction followed by ICIs) or a Combination Group (n = 45, concurrent TKI and ICIs). To minimize immortal time bias, patients in the Sequential Group had to survive the induction period. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS) and safety. Results: The sequential regimen demonstrated significantly improved survival outcomes compared to the concurrent regimen. Median OS was notably longer in the Sequential Group compared to the Combination Group (18.9 vs. 11.2 months; HR = 0.50, P = 0.0029). Likewise, median PFS significantly favored the Sequential Group (10.0 vs. 3.0 months; HR = 0.30, P < 0.0001). Subgroup analysis revealed that a shorter induction duration (≤ 2 months) provided superior PFS compared to longer induction ( > 2 months) (10.0 vs. 6.3 months; P = 0.049), highlighting the transient nature of the vascular normalization window. Additionally, the sequential approach exhibited a favorable safety profile, with numerically fewer Grade 3–4 adverse events, particularly hypertension (3.0% vs. 11.1%, P = 0.485) and gastrointestinal reactions (0% vs. 8.9%, P = 1.000), likely due to reduced overlapping toxicities. Conclusions: Our study provides the first clinical evidence that “timing matters” in combination therapy for MSS CRC. Short-course TKI induction (≤ 2 months) significantly improves survival compared to concurrent therapy. This benefit likely arises from effectively utilizing the vascular normalization window to prime the TME. Thus, a step-wise therapeutic approach emerges as a promising and less toxic treatment paradigm, challenging the conventional belief that earlier combination therapies are superior.