Patients with refractory metastatic colorectal cancer (CRC) have multiple treatment options available, yet many don't receive all approved therapies that could potentially extend their lives, according to leading oncology expert Dr. John L. Marshall.
"What shocks me on some level is the number of patients who don't end up having all three choices," said Marshall, director of the Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.
Three Key Options for Refractory Disease
Currently, three FDA-approved regimens are available for patients with refractory metastatic CRC who have progressed on standard first-line therapies:
- Trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin)
- Fruquintinib (Fruzaqla)
- Regorafenib (Stivarga)
These options are typically considered after patients have already received oxaliplatin-based therapy, irinotecan-based therapy, and appropriate biologics such as EGFR or VEGF inhibitors. For patients with specific molecular subtypes, additional targeted options may be available, including treatments for microsatellite instability-high disease, BRAF mutations, and HER2-positive disease.
SUNLIGHT Trial: A Practice-Changing Study
The SUNLIGHT trial (NCT04737187) investigated whether adding bevacizumab to trifluridine/tipiracil would improve outcomes in the refractory setting. The results were compelling, showing:
- 56% improvement in progression-free survival
- 39% improvement in overall survival
- Objective responses in some patients
"There was not only an improvement in progression-free survival and overall survival, there were also a few patients who had some response," Marshall noted.
The trial demonstrated that VEGF inhibition beyond progression remains valuable, establishing this combination as a standard of care option. The positive data from SUNLIGHT provides strong validation for using this regimen early in the refractory setting.
Sequencing Challenges in Clinical Practice
With three effective options available, the optimal sequencing strategy remains unclear, as head-to-head trials comparing these regimens have not been conducted. Marshall typically favors using trifluridine/tipiracil plus bevacizumab earlier in the treatment course, followed by fruquintinib and regorafenib, though he acknowledges that alternative approaches are reasonable.
"My bias tends to be using the [trifluridine/tipiracil]/bevacizumab in those patients early on and then saving fruquintinib and regorafenib for later," Marshall explained. "The main point is don't leave these drugs on the table."
Personalized Approach to Treatment Selection
Treatment selection should be individualized based on multiple factors:
- Prior exposure to VEGF inhibition
- Whether there has been a treatment break
- Patient preference for oral versus intravenous therapy
- Previous adverse events
"You want to not just have a routine...checkers-like approach to managing metastatic colon cancer. You want a chess-like approach," Marshall advised.
Dosing Modifications in Clinical Practice
Marshall also highlighted that experienced clinicians often modify the approved dosing schedules to optimize outcomes and quality of life. For example, with trifluridine/tipiracil, the approved schedule is two weeks on followed by two weeks off, but Marshall prefers an every-other-week approach.
"I find that difficult to use, and so I automatically go to every other week," he said. "I sometimes do modifications with fruquintinib, and we are all modifying regorafenib based on [data from] clinical trials."
Non-Medical Factors Affecting Treatment Decisions
A concerning issue in this disease setting is the influence of non-medical factors on treatment decisions. Marshall noted that pharmacy benefit managers sometimes dictate treatment sequencing based on financial rather than medical considerations.
"I might want to use one of these three drugs, but they write back and say, 'No, not until you've used the other [ones first],'" Marshall explained. "There has been some external influence, not medical but insurance based, on the sequence of our therapies."
Future Directions
Looking ahead, Marshall emphasized the need for novel therapies and targets. Emerging treatments for specific molecular subtypes, such as RAS mutation-targeted therapies, hold promise but will still leave many patients requiring additional approaches.
For the approximately 50,000 patients diagnosed with metastatic CRC annually in the United States, maximizing the use of all available treatment options remains critical to extending survival while maintaining quality of life. The key message from Marshall is clear: patients with refractory disease who maintain good performance status should be considered for all three approved regimens in sequence, with the specific order tailored to individual circumstances.
