Navigating Treatment Options for Relapsed Metastatic Colorectal Cancer in the Community

JOHN MARSHALL, MD
Clinical Director, Oncology,
Medstar Georgetown
University Hospital
Chief, Division of Hematology/
Oncology, Medstar
Georgetown University Hospital
Associate Director, Clinical
Research, Lombardi
Comprehensive Cancer Center
Washington, DC

AJMC®: What treatment options can be considered for patients with metastatic colorectal cancer (mCRC) that has progressed on frontline chemotherapy (eg, FOLFOX [leucovorin, fluorouracil (5-FU), oxaliplatin], FOLFIRI [leucovorin, 5-FU, irinotecan]) and is being treated in a community oncology setting?

MARSHALL: In the context of managing mCRC that has progressed after frontline chemotherapy, such as FOLFOX or FOLFIRI, treatment decisions become akin to a strategic chess game, where each move is tailored to the patient’s unique characteristics and circumstances. It’s crucial to have a clear understanding of the molecular profile of the cancer from the outset, distinguishing between right-sided and left-sided tumors, to guide subsequent choices. Precision medicine testing plays a pivotal role in this process. Initially, frontline therapy typically involves a combination of drugs like 5-FU, oxaliplatin, and often bevacizumab, although the specifics can vary based on individual factors. Some subsets of patients might receive frontline therapy targeting the epidermal growth factor receptor (EGFR), altering the combination of drugs accordingly.

Following frontline treatment, there’s often a shift to maintenance therapy, refining the treatment regimen to mitigate potential cumulative toxicities. For instance, transitioning from a 3-drug cocktail to a 2-drug combination by removing oxaliplatin is common.

When patients progress on frontline therapy, as your question addresses, a new set of decisions unfolds. In community oncology settings, a prevalent approach involves switching from oxaliplatin-based therapy to irinotecan-based regimens. This shift aligns with the specific molecular profile of the patient—adapting the strategy based on whether they were initially treated with bevacizumab or an EGFR inhibitor. In this metaphorical chess game of cancer treatment, we begin with our strongest pieces, customizing the approach based on individual characteristics. However, it’s essential not to overlook the importance of pawns—referring to later-stage treatment options that remain critical in the overall management strategy.

In summary, the management of mCRC during post-frontline therapy is highly nuanced and individualized. Treatment decisions are shaped by a thorough understanding of the patient’s profile, aiming not only for survival but also for maintaining quality of life throughout the treatment journey. I also want to emphasize that I dislike the term third-line therapy, because it can imply to patients that they are nearing the end of their treatment options, which is not the case. There are numerous therapies available with different mechanisms of action that can be effective for patients. Oncologists must aim to utilize all available treatments for their patients, ensuring that no potential option is left untried. This approach ensures a comprehensive strategy tailored to the individual patient’s needs and characteristics.

AJMC: What are the potential advantages and limitations of treating patients with trifluridine/tipiracil (FTD/TPI) plus bevacizumab as compared with regorafenib or fruquintinib, particularly in terms of patient outcomes and managing adverse effects?

MARSHALL: In the treatment of refractory mCRC, 3 main options are available: (1) the combination of FTD/TPI plus bevacizumab, (2) regorafenib, and (3) fruquintinib. While none offer significant tumor regression, they can stabilize disease through distinct mechanisms of action, making it important to sequence through all options. The FTD/TPI-bevacizumab regimen combines an oral chemotherapy with intravenous (IV) anti-VEGF therapy. Key advantages include the potential for synergistic antitumor activity by targeting multiple pathways. However, it carries typical chemotherapy-associated adverse events like myelosuppression, nausea, and fatigue. Regorafenib, a multikinase inhibitor hitting various pathways, was the first approved in this refractory setting. Its [adverse] effect profile is distinct, including hand-foot syndrome. Fruquintinib is the newest VEGF inhibitor option after prior antiangiogenic exposure. While more selective than regorafenib, [fruquintinib therapy is related to] expected toxicities that include hypertension, fatigue, and hand-foot syndrome. In selecting among these agents, clinicians must weigh each patient’s prior therapies, residual toxicities, comorbidities, and performance status to optimize efficacy while proactively managing anticipated [adverse] effects. An individualized approach is crucial in this difficult-to-treat population.

AJMC: How can the recent SUNLIGHT data, which support using FTD/TPI in combination with bevacizumab, impact how FTD/TPI is used in community oncology practices?¹

MARSHALL: The SUNLIGHT data present a significant shift in how FTD/TPI is viewed in community oncology. Unlike previous studies that compared these medications to placebos, SUNLIGHT directly compared FTD/TPI plus bevacizumab to an active comparator of FTD/TPI alone, providing valuable insights. This study revealed that combining FTD/TPI with bevacizumab extended survival further than [did] FTD/TPI alone, even in patients who had prior exposure to bevacizumab. These findings have influenced my practice, leading me to prioritize combination therapy whenever possible based on the SUNLIGHT data.

I believe part of the hesitation among patients and community oncologists regarding these oral agents is that patients are accustomed to regular visits for IV treatments. In a kind of reverse logic, having an every-3-week or every-2-week visit to the doctor for an IV dose of bevacizumab can be reassuring for both parties. These regular visits allow for patient assessment, [laboratory] work, and, crucially, the delivery of a better outcome than [provided by use of] FTD/TPI alone.

AJMC: How do the outcomes seen in SUNLIGHT compare with the real-world outcomes you’ve seen in your patients treated with FTD/TPI?¹

MARSHALL: In my clinical experience, the outcomes observed in patients treated with FTD/TPI align closely with those reported in the SUNLIGHT study. Many patients with long-standing metastatic disease have benefited from these therapies, experiencing significant cancer stabilization and occasional minor responses, especially if they had a break from chemotherapy prior to treatment. It’s important to note that rechallenging with traditional chemotherapy agents like oxaliplatin or irinotecan seldom leads to substantial responses. Despite some community practices leaning toward reverting to these agents, evidence supporting their efficacy in this context is limited.

AJMC: What has been your experience with providing patients with alternative dosing strategies for regorafenib, such as those used in the ReDOS trial?²

MARSHALL: The original dosing strategy for regorafenib at 160 mg daily proved challenging for some patients due to intolerance, jeopardizing treatment benefits. However, the ReDOS trial introduced an alternative approach, starting patients at a lower dose of 80 mg and gradually escalating to 160 mg if tolerated. This dose escalation strategy demonstrated improved patient adherence, satisfaction, and quality of life compared with the traditional dosing regimen. While not explicitly powered for improved outcomes, there were suggestive indications of better efficacy. Adoption of the ReDOS strategy is now recommended, supported by updated labeling. Although it requires early patient management, often achievable through telemedicine or nurse support, the benefits of optimized dosing outweigh the initial effort, leading to improved outcomes.

AJMC: What role does fruquintinib play in your management of mCRC, and how do you apply the FRESCO-2 trial data into practice?³

MARSHALL: Fruquintinib has emerged as a significant addition to the treatment options for mCRC, catching many by surprise. Initially studied in China, this oral VEGF inhibitor targets VEGF1, -2, and -3 with high potency. Early studies indicated a notable survival benefit in CRC, prompting the FRESCO-2 trial to validate these results in a Western population. The FRESCO-2 trial confirmed fruquintinib’s clear single-agent activity in improving overall survival, leading to its approval in November 2023. In practice, fruquintinib is now being integrated as a valuable option for patients with refractory mCRC. It is known for [adverse] effects such as hypertension, fatigue, and hand-foot syndrome, but its role in extending survival makes it a critical addition to the treatment arsenal. Notably, fruquintinib does not require precision-medicine enrichment, meaning it is effective regardless of tumor location (right- or left-sided) or genetic mutations such as RAS or BRAF. This broad applicability allows its use in all patients with refractory mCRC, expanding the options available for managing this challenging disease stage.

AJMC: When treating patients in the community, what strategies have been effective in enhancing patient outcomes while minimizing additional adverse effects with these third-line therapies for mCRC (eg, FTD/TPI, regorafenib, fruquintinib)?

MARSHALL: It’s vital to recognize that third-line therapies for mCRC such as FTD/TPI, regorafenib, and fruquintinib still come with [adverse] effects. Therefore, regular patient check-ins are essential to monitor both treatment efficacy and tolerability. Patients are typically accustomed to frequent visits, facilitating close monitoring. Coordination with the pharmacy to ensure timely medication delivery is crucial, as patients may experience delays in receiving their prescriptions. Upon treatment initiation, a follow-up visit within 1 to 2 weeks allows for assessment of medication adherence and early [detection of adverse] effects. In-person consultations provide an opportunity to assess patient understanding and [adherence to] dosing instructions as well as to conduct necessary laboratory tests. Subsequent visits can be spaced out based on patient stability, allowing for a balance between close monitoring and reducing visit frequency to alleviate patient burden.

AJMC: How do you incorporate patient preferences, disease stage, and overall health when developing later-line treatment plans for patients with mCRC?

MARSHALL: Developing later-line treatment plans for patients with mCRC involves considering various factors such as patient preferences, disease stage, and overall health. Again, I think of this as a chess game—and to answer this question, you first need to understand what the chess board looks like. The treatment approach depends on individual circumstances and goals. For instance, if a patient has asymptomatic cancer and plans a vacation with their family, a specific medication may be favored. Additionally, factors like prior treatment history and desired outcomes influence treatment selection. The most common strategy I see is the use of combination therapies like FTD/TPI plus bevacizumab initially. However, alternative options such as regorafenib, with its unique mechanism of action, may be chosen for patients seeking novel treatment approaches. Each treatment option offers benefits in terms of survival and progression-free survival but also brings specific [adverse] effects, necessitating careful consideration and tailored decision-making.

AJMC: With the emergence of several targetable biomarkers in mCRC, how has the landscape of precision oncology and personalized medicine evolved in community oncology settings for patients with mCRC?

MARSHALL: In the landscape of community oncology settings, precision oncology and personalized medicine have significantly evolved for patients with mCRC. Every patient with mCRC needs molecular profiling, particularly for targetable biomarkers like microsatellite instability (MSI), RAS, BRAF, and HER2. Despite advancements, [a majority] of patients with mCRC may lack proper molecular profiling, highlighting a gap in standard of care. Ensuring that all patients undergo comprehensive molecular testing is imperative to identify potential treatment targets and improve survival outcomes.

However, challenges persist, including inadequate integration of molecular testing into electronic medical records and variability in test quality and interpretation. Unlike radiological tests, where quality and interpretation are clear, molecular testing standards remain inconsistent. Therefore, clinicians must actively verify the quality and accuracy of molecular tests and ensure appropriate follow-up when necessary. Ultimately, it is incumbent upon health care providers to uphold the standard of care by staying informed and proficient in precision medicine for CRC.

AJMC: What challenges or barriers do community oncologists face when implementing precision oncology approaches in the mCRC setting?

MARSHALL: Community oncologists encounter several challenges when implementing precision oncology approaches in the setting of mCRC. First, determining which tissue to test poses a significant dilemma. Should the primary tumor be tested, or is a biopsy of metastatic sites necessary? Additionally, the viability of liquid biopsies as an alternative requires consideration. Moreover, understanding the intricacies of various tests is essential. While some tests like immunohistochemistry for MSI and HER2 may be familiar, others such as RAS and BRAF mutations demand deeper knowledge. Identifying specific mutations like G12C in RAS adds complexity. Keeping track of ordered tests within electronic medical records further complicates the process, necessitating meticulous recordkeeping to ensure [that] patients receive optimal guidance and treatment.

AJMC: Looking ahead, what do you see as the future of precision oncology and personalized medicine in community oncology settings for mCRC?

MARSHALL: In the realm of precision oncology and personalized medicine for mCRC in community oncology settings, we are currently navigating through an awkward adolescence. While we possess the necessary components, we’re still learning how to effectively utilize them. The complexity of current practices may lead to confusion and challenges for clinicians. However, looking ahead, I envision a future where precision medicine becomes more streamlined and accessible. Advances in artificial intelligence will play a significant role, assisting clinicians in making informed treatment decisions tailored to individual patients. Instead of relying on trial and error, molecular medicine will guide us toward the most effective therapies for each patient at the right time. Ultimately, I foresee a future [in which] precision oncology becomes simpler and more intuitive. As we continue to evolve, clinicians can look forward to a time when navigating treatment options for mCRC becomes more straightforward and efficient.

AJMC: What closing thoughts about the management of mCRC in the third line would you like to share?

MARSHALL: In managing mCRC in the third line, we’ve made significant strides with the introduction of new therapies. We’re actively exploring innovative approaches, such as earlier use or combination therapies, to further enhance patient outcomes. Looking ahead, there’s promising potential in optimizing immune therapies and advancing precision-medicine strategies targeting RAS and BRAF mutations. Additionally, I’m particularly excited about the increased research investment facilitated by organizations like the Colorectal Cancer Alliance. Project Cure is just 1 example of research investments that I’m particularly excited about. Similar to transformative grants in breast cancer research, this funding holds the promise of accelerating progress toward better outcomes and potential cures for [patients with CRC].

For more information about Project Cure, please visit: https://colorectalcancer.org/research/research-investments/project-cure-crc

REFERENCES

1. Prager GW, Taieb J, Fakih M, et al; SUNLIGHT Investigators. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657-1667. doi:10.1056/NEJMoa2214963

2. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4

3. Dasari A, Lonardi S, Garcia-Carbonero R, et al; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9