Best Late-Line Treatments for Metastatic Colorectal Cancer

For the patient with metastatic colorectal cancer in whom the first- and second-line therapies have failed, difficult decisions need to be made. In the late-line setting, the options currently revolve around oral targeted therapy or the oral cytotoxic agents in combination with the biologic agents. Each has its own balance of antitumor activity, toxicity, and oral administration-related convenience. Ultimately, these choices must be tempered by a vision of survivable disease that is consistent with the patient’s goals, expectations, and quality of life.

SUNLIGHT Trial (post-hoc)

Treatment-induced toxicity has been exploited as a surrogate marker for drug exposure and activity in prior clinical trials. In the SUNLIGHT trial, patients with recurrent metastatic gastric cancer treated with trifluridine/tipiracil (FTD/TPI) plus bevacizumab who developed severe neutropenia or NCD had improved survival compared to those who did not. Of 260 patients in the trial, 160 patients (61%) experienced severe neutropenia/NCD and had a median overall survival of 14.88 months. This was significantly improved compared with the 100 patients (39%) who experienced non-severe or no neutropenia and had a median overall survival of 8.28 months.

Why It Matters

One of the most difficult clinical decision points for patients with metastatic colorectal cancer is at the time of progression after initial treatment with chemotherapy and/or targeted therapy. Although the prognosis is poor at this point, numerous effective options for late-line treatment of metastatic colorectal cancer are available. The additional efficacy for these treatments is modest at best, but the pharmacologies are distinct and toxicities, some of which are dose limiting, are not equivalent. As a result, the choice of these agents and their sequencing will require consideration of patient-oriented factors and an assessment of the use of health-system resources including infusion time, required supportive care and treatment cost.

Patients

For patients on the therapy “radar screen” for late-line, what are some of their major considerations? To achieve progression free duration of time, even if it is only for several more months, to have other options to come off of treatment Induction and/or off of IV meds, among others. Importantly, all late-line regimens include medications for which treatment tolerability is paramount, as patients are already very weakened from their prior therapies (months, years). The remaining bone marrow reserve, organs and performance status will dictate both risk and potential benefit of each option.

Healthsystems

Systems, particularly systems of payment and delivery, will be challenged. With an increasingly robust approved therapeutic options portfolio, fewer treatments will require dedicated infusion suites (due to administration by mouth) but more will pose challenges to adherence, out-of-pocket costs, and pharmacy benefit management. Challenges also will arise due to treatments that combine infusion with oral therapies. Policymakers and payers will strive to ensure timely and equitable access to effective therapies for patients with relapsed or refractory lymphoma some of whom have received prior therapies.

What the data says

Patients who developed severe neutropenia had longer overall survival (approximately 14 months) compared with those who developed either non-severe neutropenia or no neutropenia (overall survival approximately 8 months) regardless of treatment arm. In the patients treated with FTD/TPI monotherapy severe neutropenia was associated with improved overall survival. While FTD/TPI and bevacizumab resulted in treatment-related toxicity, severe neutropenia in this setting is a favorable sign indicating that the patient is achieving effective drug levels. Thus, typical Oncology wisdom to avoid adverse effects is inverted in this clinical setting.

Who It Affects

Patients

The decisions regarding treatment of metastatic colorectal cancer would generally pertain to patients whose disease has progressed after prior chemotherapy and/or targeted therapy. However, the ultimate decision would also take into consideration several other factors, including the tumor biology and presence of actionable biomarkers such as mismatch repair deficient or other targetable mutations. The patient’s prior exposure to anti-VEGF or anti-EGFR therapies, as well as the patient’s current medical status and goals of care would also play important roles in decision making.

Clinicians

Healthcare professionals at all levels of oncology practice – from major academic centers to smaller community-based oncology practices (public and private) including medical and surgical oncologists, patient care coordinators (such as nurses), hospitalists, and others involved in patient care in the infusion center – use this information to guide patients and families through their treatment decisions for subsequent lines of therapy. This information is used to make a variety of practice and patient management decisions, including those affecting patients and families, healthcare providers and all levels of staff involved in delivering patient care, in order to increase or decrease the volume and intensity of care delivered in the infusion setting, to modify the frequency of clinical visits and level of monitoring of patients and effects of treatment.

Early-cycle neutropenia is likely to be a marker of effective treatment and patients and their families will find this reassuring. This work provides an important new tool for patient education for clinicians. As outlined in the paper, oncology teams can choose to use G-CSF in order to achieve both maximized drug levels and scheduling, while avoiding the potential for toxic consequences that could negatively affect patient quality of life.

Payers and Pharmacy Benefit Managers (PBMs)

The main stakeholders in this scheme are the patients, of course. But patients are not alone. Payers (commercial insurance companies as well as Medicare and Medicaid) and Pharmacy Benefit Managers (PBM’s) are also stakeholders. Because the newer oral agents are expensive, the payer might weigh the cost of the new oral agent against either very frequent glucose monitoring (e.g., multiple daily glucometer readings, or continuous glucose monitoring or sensor data) or very expensive intensive basal insulin therapy. The payer would then decide whether or not to cover the newer agent (if it considers the treatment to be medically necessary), and what portion of its cost the patient must pay. Even if a patient assistance program (PAP) is available for a particular agent, certain patients may be denied assistance (or find that they are denied assistance, with little or no explanation, even after they have applied through the patient assistance program website). Others may be delayed in receiving prior authorization.

Managing Adverse Effects without Compromising Dose Intensity

Management of adverse events is important to maximize the benefit of single-agent alectinib. Neutropenia, including NCD, usually occurs within the first two cycles of treatment. Severe neutropenia seldom required permanent dose reduction or permanent discontinuation. Severe neutropenia mostly occurred early during treatment in the SUNLIGHT study, and most cases resolved within a median of 8 days.

Reduction of chemotherapy doses for patients with leukaemia with low white blood cell count is not always necessary. Dose reductions can be avoided by administering granulocyte colony-stimulating factor (G-CSF). Clinical data indicate that by keeping dose intensity constant, based on the applicable pharmacokinetic data, superior survival can be achieved. In this study, G-CSF was given thromboprotectively in the first two cycles of chemotherapy and as secondary prophylaxis in all following cycles.

What Changes

• Shift toward individualized sequencing: clinicians prioritize a patient’s goals, prior treatments, and organ function when choosing among oral monotherapy, oral targeted therapy, or an oral cytotoxic agent combined with a biologic infusion.
• Greater emphasis on toxicity management and supportive care: strategies such as growth factor support for low white blood cell counts, proactive management of blood pressure and skin reactions, and close monitoring aim to keep patients on effective regimens longer.
• Growing role for oral options and outpatient care: more treatments are available in pill form, reducing the need for infusions but increasing the importance of adherence monitoring and pharmacy coordination.
• Policy and access implications: coverage, out-of-pocket cost, and geographic variability in specialty care influence which options patients receive in real-world practice.

Expanded Considerations

When treating patients with metastatic colorectal cancer (mCRC) beyond the 5-FU containing regimen, there are typically trade-offs associated with each different class of treatment. Patients and their physicians can receive the benefits of oral cytotoxic chemotherapy as well as the benefits associated with targeting the blood-vessel connections that tumors require for growth (tumor angiogenesis) by using a combination of an oral cytotoxic agent and a VEGF-targeting biologic. The combination of these two classes of treatment provides the patient the benefits of an oral backbone chemotherapy and the additional benefit of targeting the tumor with a biologic to specifically target the angiogenic pathway. Furthermore, there are oral anti-angiogenic options that can be used without the need for any infusions; however, these agents have their own toxicity profile and must be monitored in the outpatient setting.

Bone Marrow Suppression

Bone marrow suppression remains a major toxicity of the late-line cytotoxic therapies. Many of these drugs are known to be associated with the development of neutropenia, and an assessment of the absolute neutrophil count (ANC) is typically performed. Interestingly, some have used the development of neutropenia as an indicator of biologic activity for these drugs. Therefore, they recommend not reducing the dose for the first episode of low counts, but rather using growth factor support with G-CSF to allow for continued dose intensity in patients tolerating other toxicities well.

Other treatment-related adverse events will also influence patients’ choices between oral and parenteral multi-kinase inhibitors. For the oral multi-kinase inhibitors, fatigue, hypertension, and skin toxicity may be dose-limiting. The biologic agents can cause hypertension and proteinuria and require visits to infusion centers. A variety of factors will need to be weighed in considering these trade-offs including evidence-based information, patients’ preferences for clinic visits and travel, and other aspects of treatment burden.

Therapy Choices and Order

Some agents are indicated based on prior therapy. These agents are used after other specific therapies on the basis of available clinical data, approved indications, or both. Prior therapy can influence an agent’s use, as well as treatment decision. In turn, prior therapy can determine the sequence in which therapies are given. “An oral targeted agent may be chosen because a patient does not want to receive an infusion,” Schilsky says. “Another agent may be given with other therapies to maximize disease control, even if it means patients have to go to infusions for administration.”

Clinical Decision-Making and Patient Conversations

Shared decision-making. Clinicians need to present the likelihood of benefits and risks (including disease control and quality of life) and avoid drawing too much attention to relatively small gains in survival. Clinicians and patients must also discuss the potential toxicities and the intensity of monitoring and follow up. Before and during treatment, patients and clinicians should discuss these issues to come to a shared understanding of priorities for management of metastatic disease. These priorities could be (1) longest duration of disease control, (2) least number of clinic visits, (3) alleviation of symptoms, or (4) preservation of function. On the basis of these priorities, different treatments may be selected or modified.

Of course, many practical factors may affect our decision. Blood counts and liver function tests, prior treatment toxicity, the presence of metastases to critical sites (like the liver), and psychosocial factors, such as the patient’s and family’s ability to attend and return for scheduled treatments on time and have adequate support at home, may all play a role. Some patients with poor bone marrow reserve may not tolerate as much marrow toxic therapy. Some patients who live far from our infusion centers may prefer an oral approach because of travel time to and from the infusion center.

System-Level and Policy Implications

Health systems require sufficient capacity to infuse patients as well as sufficient capacity of outpatient pharmacy for late-line treatment of leukemia patients. Providers and payers are seeking streamlined prior authorization for critical supportive care services like growth factor and hematology monitoring. Decisions regarding coverage of expensive oral therapies (e.g. venetoclax) versus oral plus additional infusion-based therapies (e.g. venetoclax plus blinatumomab) are particularly challenging for payers.

Affordability raises issues of equity for individuals and families in rural and resource-poor populations seeking effective treatment for BD. Reducing the cost of medication, and expanding access to telehealth as well as home-based supportive treatment and services can help address this critical issue.

What Comes Next

Late treatment strategies for lung cancer: What’s trending? Better biomarkers to predict which patients are most likely to benefit from which therapies. Real-world evidence and long follow-up of promising emerging therapies. Optimizing dosing and supportive care to maximize benefit while minimizing toxicity.

Future of Clinical Research

While future clinical studies are anticipated to elucidate optimal combinations and timelines for administration of these targeted therapies, an immediate challenge will be to integrate current options into an individualized treatment plan for each patient with follicular lymphoma. Practical and accessible clinical guidelines need to be translated into practice, equipping clinicians to manage toxicities, provide supportive care, and educate payers regarding evidence-based sequential and combination therapies most important to patients and their families.

Patients and Clinicians

Late-line metastatic colorectal cancer has delivered some good news—albeit with a few caveats—for both patients and their clinicians. For many patients, third-line therapy is not the only option, and effective disease control can be achieved for a significant period, perhaps longer than many providers or patients realize. To that end, the key will be for both to do their best to select a treatment and supportive care approach that fits within the patient’s medical situation, their preferences, as well as issues of access and cost.

Reference

1. 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