Trifluridine/Tipiracil-Associated Neutropenia Associated With Improved Outcomes in mCRC

Trifluridine/tipiracil (Lonsurf) plus bevacizumab (Avastin) demonstrated a correlation between treatment-induced severe neutropenia and improved clinical outcomes in patients with later-line metastatic colorectal cancer (mCRC), according to findings from a post hoc analysis of the phase 3 SUNLIGHT trial (NCT04737187).

In a conversation with Marwan G. Fakih, MD, he noted that while the relationship between hematologic toxicity and efficacy was previously debated, recent data suggest that neutropenia serves as a critical pharmacodynamic biomarker indicating adequate systemic exposure and cytotoxic activity.

The association between neutropenia and survival benefit with trifluridine/tipiracil monotherapy has long been a subject of clinical debate, specifically whether the toxicity is a precursor to response or merely a result of prolonged treatment exposure. Fakih observed that the SUNLIGHT trial illuminated this “chicken or egg” scenario by analyzing neutropenia occurrence as early as the first cycle of therapy.

Crucially, patients who developed significant neutropenia during the first cycle, prior to the initiation of G-CSF support, were more likely to derive a deeper therapeutic benefit. This suggests that a drop in the absolute neutrophil count serves as a surrogate for the drug’s impact on rapidly dividing cells, including the tumor itself.

The identification of neutropenia as a positive prognostic indicator has significant implications for toxicity management. Rather than viewing severe neutropenia as a mandate for dose reduction, Fakih argued for the proactive use of supportive care to maintain treatment intensity.

He further cautioned against misinterpreting these results to justify dose escalation in patients who do not exhibit neutropenia.

Fakih is a professor in the department of Medical Oncology and Therapeutics Research, the deputy director of City of Hope Comprehensive Cancer Center, medical director for Briskin Center for Clinical Research, and division chief of Gastrointestinal Medical Oncology and co-director of the Gastrointestinal Cancer Program at City of Hope.

Transcript:

CancerNetwork: Patients who received trifluridine/tipiracil plus bevacizumab experienced improved outcomes when they had severe neutropenia. What do these results mean?

Fakih: The question of neutropenia and benefit from [trifluridine/tipiracil] has been asked before with [trifluridine/tipiracil] monotherapy, in that there had been data suggesting that patients who developed significant neutropenia had better results with [trifluridine/tipiracil] compared with best supportive care. In the past, there has been a lot of debate; however, we ask if it is the chicken or the egg. Is the fact that you’re having neutropenia going to imply that you’re going to get a better response? Or is it the fact that, because you responded better to therapy, you stayed longer on the treatment, and you’re getting neutropenia?

The nice thing about SUNLIGHT is that we shed some light on that. If you do get neutropenia, even on the first cycle where you haven’t really used G-CSF yet, you’re more likely to derive a benefit that is deeper. That’s an important finding. It doesn’t mean you need to make your patients sick to get a benefit, but it means that neutropenia is a pharmacodynamic biomarker of adequate dosing. If you do get neutropenia with the standard dosing, that means that you’re probably also having a better cytotoxic effect on your cancer cells. Now, it doesn’t mean that we should consider higher dosages for those who don’t have neutropenia. That would be a no-no because no one has tested that safety strategy, but to me, what it means is that if somebody develops neutropenia and otherwise does not have any other [adverse] effects, I, as a treating physician, would favor considering G-CSF support on that individual rather than reducing the dose. The patient is tolerating the treatment well, and you can fix the neutropenia, especially when that neutropenia is a biomarker of benefit. Perhaps it tells us that dosing is important. A dosing regimen that has a pharmacodynamic end point that is notable, such as low [white blood cell] count and low [neutrophil] count, may also be important in efficacy.

Reference

Prager GW, Elez E, Fakih MG, et al. Association between neutropenia and efficacy in patients with refractory mCRC receiving trifluridine/tipiracil + bevacizumab: post hoc analysis of the SUNLIGHT trial. ESMO Gastrointest Oncol. 2025;10:100234. Published online September 8, 2025. doi:10.1016/j.esmogo.2025.100234