Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer

Abstract

Background: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility.

Methods: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint.

Results: Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3-19.7) and 3.9 months (95% CI, 2.3-5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9-14.7) for control arm patients (N = 31).

Conclusions: Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases.

Trial registration: ClinicalTrials.gov number, NCT03388190 (02/01/2018).

Fig. 1. Flow diagram of the selection of cases for the current study.

Out of 80 screened patients, 76 were randomised to receive either eight cycles of the Nordic FLOX regimen Q2W (control arm) or two cycles of FLOX Q2W followed by two cycles of nivolumab Q2W in a repeat sequential schedule to a total of eight cycles (experimental study arm). 31 patients in the control arm and 35 patients in the experimental study arm reached the first response assessment after 8 weeks of treatment.

Fig. 2. Target lesion (TL) changes for individual patients.

Grey columns represent the first post-baseline response assessment, which for 14 (45.2%) control arm cases (N = 31) and 11 (31.4%) experimental-arm cases (N = 35) was the best overall response. Black columns represent the overall TL changes for the remaining cases. Symbols: circle, the patient had discontinued the study treatment before the second response assessment; star, the patient had experienced complete response of TL lymph node metastases.

Fig. 3. Time until the deepest target lesion reduction for the individual patients (dots) in control (N = 29) and experimental (N = 25) study arms.

Vertical lines indicate the median values. Cases of only target lesion increase were excluded from this analysis.

Fig. 4. Kaplan–Meier curves for progression-free survival.

Shown for all control arm patients (N = 35; upper panel a) and experimental-arm patients (N = 37; lower panel a) eligible for the present analysis, with shading reflecting the 95% confidence interval, and for the patients who reached the first post-baseline response assessment (b) stratified as control arm patients (N = 31; blue curve) and experimental-arm patients with ≥10% target lesion (TL) reduction (N = 19; pink curve) or <10% reduction (N = 16; black curve; star, the referred case participating in the magnetic resonance imaging programme of liver metastases).