In what is believed to be the largest real-world comparison, overall survival was similar in patients with refractory metastatic colorectal cancer (CRC) who received regorafenib (Stivarga) or trifluridine/tipiracil (TAS-102; Lonsurf) after at least two prior lines of therapy.
The modest median overall survival gains seen with these oral agents aligned with those observed in the clinical trials that led to US approval, and these real-world findings suggest that the moderate benefit of these agents is not lost in a real-world population, said the authors, led by Christopher Nevala-Plagemann, MD, of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.
The study was published online February 22 in the Journal of the National Comprehensive Cancer Network.
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The 2012 Food and Drug Administration approval of regorafenib was based on the phase 3 CORRECT trial, which showed a modest improvement in median overall survival using regorafenib compared with best supportive care plus placebo (6.4 vs 5 months; hazard ratio [HR], 0.77). In 2015, the FDA approved TAS-102 based on the phase 3 RECOURSE trial, which showed a similarly modest overall survival benefit using TAS-102 compared with best supportive care plus placebo (7.1 vs 5.3 months; HR, 0.68).
However, no head-to-head prospective studies have compared outcomes with these two agents and current National Comprehensive Cancer Network guidelines don’t state a preference for one over the other.
To compare real-world overall survival outcomes with regorafenib and TAS-102, the Utah researchers used the Flatiron Health database to identify 1937 patients diagnosed with metastatic CRC between 2015 and 2020. All patients had received at least two lines of standard systemic therapy followed by regorafenib and/or TAS-102.
In a treatment trends analysis, excluding year 2015 (right after TAS-102 approval), use of TAS-102 and regorafenib appeared to be “relatively equal,” ranging from 12% to 20% of therapies administered, the authors reported.
Overall, 921 (47.5%) patients received TAS-102 alone or prior to regorafenib (TAS-102 group) and 1016 (52.5%) received regorafenib alone or prior to TAS-102 (regorafenib group).
In the survival analysis, median overall survival for the TAS-102 group was 6.6 months compared with 6.3 months for the regorafenib group — similar to the clinical trial findings. A propensity score-weighted analysis controlling for potential confounders did not find a significant difference in survival between the groups (hazard ratio, 0.99).
In an exploratory subgroup analysis, the authors also found no significant differences in survival when stratifying patients by age, performance status, RAS/RAF status, microsatellite instability status, primary tumor sidedness, or prior targeted therapy receipt.
In addition, the sequence of therapy in patients who were fit enough to receive both TAS-102 and regorafenib did not appear to impact survival outcomes. Survival outcomes were similar among the 111 patients who received regorafenib after TAS-102 and the 99 patients who received TAS-102 after regorafenib (HR, 0.98; 95% CI, 0.83-1.14).
Nevala-Plagemann and colleagues explained that this real-world comparison is “important because these drugs will likely never be compared directly in a head-to-head prospective trial.”
Given similar overall survival benefits, the choice of agent for eligible patients should be individualized, with a focus on the differences in toxicity and schedule of administration of each drug, the researchers suggest.
Regorafenib, given daily for 21 days of a 28-day cycle, has been shown to lead to higher rates of grade 3 hand-foot syndrome, fatigue, hypertension, and hepatotoxicity compared with TAS-102. Since the initial approval, however, modified dosing strategies have led to improved tolerability of regorafenib. TAS-102, administered on days 1-5 and 8-12 of a 28-day cycle, may come with a higher incidence of hematologic toxicity, particularly neutropenia.
“These data should be considered when discussing the risks and benefits of TAS-102 and regorafenib with patients who are eligible for third-line or greater treatment,” the researchers said.
And given the modest survival benefits of both agents, the authors expressed the need for novel therapeutic options for patients with refractory metastatic CRC. On that front, a recent phase 2 study showed improved progression-free survival with the combination of TAS-102 plus bevacizumab compared with TAS-102 alone in patients with refractory metastatic CRC (HR, 0.45) as well as a modest improvement in median overall survival with the combination (9.4 vs 6.7 months).
Additional trials evaluating the benefit of TAS-102 plus bevacizumab and investigating other combinations with TAS-102 or regorafenib are underway and “we are hopeful that these studies will lead to further improvements in outcomes of patients diagnosed with mCRC,” the authors said.
The current study was supported by the Foundation for the National Institutes of Health. The authors report no relevant financial disclosures.
J Natl Compr Canc Netw. Published online February 22, 2023. Full Text.
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