Dr Lieu on Mapping Third-Line Treatment Strategy in mCRC

"Whenever we map out the third-line strategy for a patient with refractory mCRC, the biggest focus is on how our patient is doing, what their performance status is, and what are some of the toxicities that they’ve received from their prior therapies. We also want to take a good look at their molecular information.”

Christopher Lieu, MD, codirector of the Gastrointestinal Medical Oncology Program, associate director for clinical research, and a professor of medicine in the Department of Medical Oncology at the University of Colorado Cancer Center, discussed key considerations when determining the optimal third-line treatment strategy for patients with refractory metastatic colorectal cancer (mCRC).

When patients reach the third-line setting, the clinical objective often transitions from achieving a major objective response, which is less likely in the refractory setting, to stabilizing the disease, Lieu noted. Mapping a third-line strategy accordingly requires a highly individualized assessment of the patient’s performance status, their personal goals, and the specific toxicities they have accumulated from prior lines of therapy, Lieu stated. Oncologists must also conduct a thorough review of molecular biomarkers to ensure that opportunities for targeted therapy have not been overlooked. For instance, if a patient’s disease is HER2-amplified, they should be evaluated for treatment with targeted regimens such as tucatinib (Tukysa) and trastuzumab (Herceptin) or fam-trastuzumab deruxtecan-nxki (Enhertu).

Standard systemic options for the third line typically include trifluridine/tipiracil (TAS-102; Lonsurf) in combination with bevacizumab (Avastin) and regimens involving fruquintinib (Fruzaqla) or regorafenib (Stivarga). Lieu explained that selecting between these agents is largely informed by the patient’s prior toxicity profile. If a patient has significant bone marrow issues or cytopenias resulting from previous chemotherapy, adding another cytotoxic agent may be inappropriate. Conversely, for patients with cardiovascular concerns such as hypertension, oncologists may steer away from drugs like fruquintinib—which can exacerbate high blood pressure—in favor of an agent with a different adverse effect profile. Ultimately, Lieu concluded that third-line selection is a balance of efficacy and the preservation of quality of life.