The Impact in Quality of Life of Adverse Events With Systemic Therapies for Metastatic Colorectal Cancer Previously Treated With Standard Therapies and Biologics in the United States

Systemic therapies for metastatic colorectal cancer (mCRC) have distinct safety and tolerability profiles. Adverse events (AEs) may occur and compromise the course of treatment, increase health care utilization and costs, and worsen patients’ quality of life (QoL). A recent study compared the management costs of grade ≥ 3 AEs associated with fruquintinib, trifluridine/tipiracil (T/T), regorafenib, and T/T+bevacizumab (T/T+bev) for the treatment of mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (standard therapies hereafter) and biologics in the US. The study found that fruquintinib was associated with the lowest grade ≥ 3 AE management costs. In mCRC, maintaining QoL is an important treatment goal alongside increasing survival, but the impact of AEs associated with systemic therapies for mCRC has not be characterized.

In this study, we estimated the QoL impact of AEs associated with fruquintinib, T/T, regorafenib, and T/T+bev for the treatment of mCRC previously treated with standard therapies and biologics in the US.

EuroQoL-5-Dimension-5-Level (EQ-5D-5L) patient-level data (assessing mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) from the phase 3 randomized clinical trial (Ph3 RCT) FRESCO-2, comparing fruquintinib + best supportive care (BSC) vs placebo+BSC, were analyzed using the US-specific value set. Health utility represents a preference-based measure of health-related QoL, measured on a 0 (health state equivalent to death) to 1 (full/perfect health) scale. Univariate and multivariate mixed-effects, repeated-measures, linear regression models were conducted with random intercept for each patient. Fixed predictors included randomized treatment, baseline age, sex, baseline utility, and prior treatment. Time-variant health state covariates included disease progression status and ongoing grade ≥ 3 AEs. Grade ≥ 3 AE rates for each systemic therapy were from Ph3 RCTs FRESCO and FRESCO-2 for fruquintinib (61.2% and 63.0%), CORRECT for regorafenib (78.0%), RECOURSE and SUNLIGHT for T/T (69.0% and 69.5%), and SUNLIGHT for T/T+bev (72.4%).

The mean utility score for patients who were both progression-free and free of grade ≥ 3 AEs was 0.7512. None of the fixed predictors reached statistical significance, including randomized treatment. Disease progression and ongoing grade ≥3 AEs were associated with statistically significant utility decrements, 0.0588 (P <0.0001) and 0.1385 (P <0.0001), respectively. The coefficient for ongoing grade ≥ 3 AEs was multiplied by the grade ≥ 3 AE rate of each comparator to estimate their AE-associated utility decrement. The resulting AE utility decrement was 0.085 and 0.087 for fruquintinib (based on FRESCO and FRESCO-2, respectively); 0.108 for regorafenib; 0.096 for T/T (based on RECOURSE and SUNLIGHT); and 0.100 for T/T+bev.

The impact of AEs associated with systemic therapies for mCRC is significant; the utility decrement associated with ongoing grade ≥3 AEs was more than double that of disease progression. Fruquintinib was associated with lower AE- associated QoL decrement versus regorafenib, T/T, and T/T+bev for US patients with mCRC previously treated with standard therapies and biologics. Population health and healthcare plans decision makers may consider the findings of this study when reviewing formulary/pathway choices of systemic therapies for mCRC, supplementing the previously published evidence that fruquintinib was associated with lower grade ≥ 3 AE management costs compared with regorafenib, T/T, and T/T+bev in the US.

Funding Statement:

This analysis was funded by Takeda Pharmaceuticals America Inc., Lexington, MA.

Disclosures:

V.P., T.P., Y.T., and L.H. report employment and stock ownership (Takeda). J.K. reports grants or contracts to their institution from Genentech, Bristol Myers Squibb, Amgen, Isofol Medical, Novartis, Tempest Therapeutics, MedImmune/AstraZeneca, AbbVie, MedImmune, Icon, and Turning Point Therapeutics. A.S. reports participation on an advisory board for Pfizer. M.K. and I.P. report employment (Evidera).

Authors:

Yuen Tsang, PharmD, MPH, BSc¹; Victoria Paly, MHS¹; John Krauss, MD²; Ardaman Shergill, MD³; Thihan Padukkavidana, PhD¹; Stanimira Krotneva, MSc⁴; Irina Proskorovsky, MSc⁵; Luis Hernandez, PhD MPH MSc¹

Affiliations:

¹Takeda Pharmaceuticals America, Inc., Lexington, MA, USA

²The University of Michigan Health Rogel Cancer Center, Ann Arbor, MI, USA

³University of Chicago, Biological Sciences Division, Chicago, IL, USA

⁴Evidera, Toronto, Ontario, Canada

⁵Evidera, a part of Thermo Fisher Scientific, Madrid, Spain