Efficacy and safety in early-phase clinical trials for refractory colorectal cancer: A meta-analysis

Background: Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE.

Methods: The PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2021. Trials reporting on new therapies for treatment-refractory mCRC were included.

Results: The search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 and 36 % in phase 2 trials. CBR increased from 23 % in 2010-2012 to 42 % in 2019-2021. Compared to 2010-2012, trials in 2019-2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments.

Conclusions: Treatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies.