Should we optimize cytotoxic therapy by dosing to neutropenia? Lessons from TAS-102
Authors: P.M. Kasi, A. Grothey
Journal: Annals of Oncology (2020)

In the last decade, several predictive markers of efficacy of biologic agents in the management of various malignancies in general, and colorectal cancer in particular, have made inroads into clinical practice. RAS and BRAF mutations have found to be negative predictive markers for the use of epidermal growth factor receptor (EGFR) antibodies. On the other hand, BRAFV600E mutation in colorectal cancer is a positive predictive marker for the efficacy of a triplet combination of inhibitors of EGFR, BRAF, and MEK.1Kopetz S. Grothey A. Yaeger R. et al.Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer.N Engl J Med. 2019; 381: 1632-1643Crossref PubMed Scopus (641) Google Scholar Similarly, microsatellite instability or mismatch repair (MSI/ MMR) status serves as predictor for the activity of anti–programmed cell death protein-1 (anti-PD-1), with or without cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies.2Le D.T. Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (6158) Google Scholar The most commonly used agents in the medical management of colorectal cancer, though, are still cytotoxic agents for which no reliable predictive markers have been identified. In this issue of Annals of Oncology, Yoshino and colleagues report on an on-treatment predictive marker for the oral cytotoxic agent TAS-102.3Yoshino T. Cleary J.M. Van Cutsem E. et al.Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.Ann Oncol. 2020; 31: 88-95Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar TAS-102 (trifluridine/tipiracil) is an antimetabolite currently approved for patients with refractory metastatic colorectal and gastric cancers.3Yoshino T. Cleary J.M. Van Cutsem E. et al.Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.Ann Oncol. 2020; 31: 88-95Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar When the RECOURSE trial, which established the efficacy in colorectal cancer, was initially reported in 2015, there were no known predictive markers.4Mayer R.J. Van Cutsem E. Falcone A. et al.Randomized trial of TAS-102 for refractory metastatic colorectal cancer.N Engl J Med. 2015; 372: 1909-1919Crossref PubMed Scopus (845) Google Scholar The drug appeared to have activity across the spectrum of colon and rectal cancers regardless of sidedness (left versus right colon cancer), location (colon versus rectum) or mutations (RAS-mutant versus RAS-wild-type). However, as noted in the original landmark study, the improvement in overall survival (OS) with TAS-102 versus placebo was modest (7.1 months versus 5.3 months; hazard ratio 0.68 [95% confidence interval, 0.58 to 0.81; P < 0.001]).4Mayer R.J. Van Cutsem E. Falcone A. et al.Randomized trial of TAS-102 for refractory metastatic colorectal cancer.N Engl J Med. 2015; 372: 1909-1919Crossref PubMed Scopus (845) Google Scholar Interestingly, in the same year the drug was approved, our group noted that patients who had delays in starting their next cycle of therapy were also the ones who appeared to derive benefit from the drug. Looking into reasons for the treatment delay, it became apparent that these patients experienced chemotherapy-induced neutropenia (CIN).5Kasi P.M. Kotani D. Cecchini M. et al.Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study.BMC Cancer. 2016; 16: 467Crossref PubMed Scopus (53) Google Scholar Arbitrarily choosing 1 month (post-1 cycle) as the cutoff, individuals who were having CIN post-1 cycle of therapy (CIN-1month) more often responded to the drug and had a significantly better overall survival (OS median 14.0 months versus 5.6 months; log-rank P value < 0.0001).5Kasi P.M. Kotani D. Cecchini M. et al.Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study.BMC Cancer. 2016; 16: 467Crossref PubMed Scopus (53) Google Scholar This was corroborated in the same year by analyses of the phase II and phase III clinical trials with TAS-102 in colorectal cancer, with the current study representing the combined analysis of these findings. Interestingly, the results are very consistent across the initial retrospective study and the later analysis of the prospective phase II and III studies. The underlying biologic mechanisms for the correlation between neutropenia and efficacy of this cytotoxic agent are not completely clear (see Figure 1). In the analysis by Yoshino and colleagues, a higher area under the curve (AUC) of plasma levels of trifluridine was associated with a trend toward better outcome, indicating that patient-based pharmacokinetic parameters could influence outcome. Figure 1 details additional tumor-related factors which could contribute to the observed interaction between on-treatment neutropenia and outcome. The observation that individuals who experience CIN (not neutropenic fever) have better outcomes has been corroborated across many different tumor types utilizing various cytotoxic agents and regimens. It is important to note that developing ‘neutropenia’ is different than ‘neutropenic fever’. The former is a laboratory phenomenon without deleterious clinical consequences and patients are mostly asymptomatic.6Kasi P.M. Grothey A. Chemotherapy-induced neutropenia as a prognostic and predictive marker of outcomes in solid-tumor patients.Drugs. 2018; 78: 737-745Crossref PubMed Scopus (23) Google Scholar Similar on-treatment clinical phenomena correlated with better outcome have been reported for patients who experience hypertension on anti-vascular endothelial growth factor (anti-VEGF) agents or develop severe rash with anti-EGFR agents.7Van Cutsem E. Labianca R. Bodoky G. et al.Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.J Clin Oncol. 2009; 27: 3117-3125Crossref PubMed Scopus (372) Google Scholar,8Dahlberg S.E. Sandler A.B. Brahmer J.R. et al.Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599.J Clin Oncol. 2010; 28: 949-954Crossref PubMed Scopus (208) Google Scholar Unfortunately, it lies in the nature of on-treatment predictive markers that they do not allow for pretreatment selection of patients who will eventually benefit the most from a certain intervention. Some interesting pharmacogenomic analyses have been conducted to identify patients who are more likely to develop neutropenia on TAS-102. Suenega et al. showed that individuals with variations in genes involved in metabolism and excretion of the active drug, trifluridine, had a better progression-free survival and overall survival.9Suenaga M. Schirripa M. Cao S. et al.Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer.Eur J Cancer. 2017; 86: 197-206Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar The same group also reported in the Annals of Oncology a correlation between defects in the homologous recombination pathway and clinical outcomes.10Suenaga M. Schirripa M. Cao S. et al.Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer.Ann Oncol. 2017; 28: 1015-1022Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The findings by Yoshino and colleagues have important implications and have already led to changes in the prescriber instructions for TAS-102. When the drug was initially approved, dose reductions were recommended for patients with severe CIN. Subsequently, the recommendation was modified to state that TAS-102 could be continued at the same dose as long as there were no other concerns from an infection standpoint and if it was neutropenia alone, without neutropenic fever. White blood cell growth factor support [granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF)] was also included in the updated recommendations to preserve the relative dose intensity of TAS-102. Beyond these guidelines for clinical practice the question remains as to whether patients who after 1 month of therapy with TAS-102 have not developed neutropenia the dose should be escalated to subsequently induce neutropenia with an absolute neutrophil count below a certain cutoff. This approach would need to be tested in prospective clinical trials, revisiting an old ‘dose-to-nadir’ concept to optimize dosing of cytotoxic agents for individual patients.11Wilson W.H. Grossbard M.L. Pittaluga S. et al.Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy.Blood. 2002; 99: 2685-2693Crossref PubMed Scopus (263) Google Scholar There is no funding source for this work.