Safety, Functionality, and Overall QOL Considerations in Third-Line KRAS-Mutant CRC

Systemic treatment options for patients with KRAS-mutant metastatic colorectal cancer (mCRC) who progress after 2 lines of therapy have modest survival benefits and patients are often functionally compromised after multiple prior lines of treatment.

During a live event, Christopher Lieu, MD, discusses how these factors necessitate a careful comparison of efficacy vs toxicity and quality of life (QOL) issues when selecting a treatment course in this setting. Accordingly, Lieu, an associate professor and co-director of the Gastrointestinal Medical Oncology Program at the University of Colorado Cancer Center in Denver, and participants discussed efficacy, safety, QOL, and functional outcomes data in third-line KRAS-mutant mCRC.

This is the second of 2 parts. Read part 1.

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CASE SUMMARY

• The patient is a 64-year-old man with mCRC diagnosed 2 years ago.
• Primary tumor in ascending colon with liver metastases and peritoneal implants
• Medical history: atrial fabulation; chronic obstructive pulmonary disease
• KRAS G12D mutation; microsatellite stable; low tumor mutational burden
• Current status: grade 1 bone fatigue; ECOG performance status, 2
• Laboratory values (3 weeks post last infusion): absolute neutrophil count 1.1 × 10⁹/L and platelets 98 × 10⁹/L
• First-line: FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) plus bevacizumab (Avastin); progression after 9 months; grade 2 neuropathy
• Second-line: FOLFIRI (leucovorin calcium, 5-fluorouracil, and irinotecan) plus bevacizumab; progression after 7 months; grade 2 diarrhea

DISCUSSION QUESTIONS

• How do you balance efficacy expectations against toxicity management in later lines of therapy?
• How do you manage treatment for patients who develop grade ≥2 cytopenias

EVENT RECAP

Attendees were asked to select their preferred third-line therapy for this patient, with options including fruquintinib (Fruzaqla); regorafenib (Stivarga); trifluridine/tipiracil (Lonsurf) plus bevacizumab; and trifluridine/tipiracil monotherapy. The participants were fairly evenly split between fruquintinib and trifluridine/tipiracil plus bevacizumab.

Participants compared efficacy data for these 2 options in the third-line setting, while acknowledging the limitations of cross-trial comparisons.

Results from the phase 3 SUNLIGHT trial (NCT04737187) showed that trifluridine/tipiracil plus bevacizumab yielded a median overall survival(OS) of 10.8 months vs 7.5 months with trifluridine/tipiracil alone (HR, 0.61; 95% CI, 0.49-0.77; P < .001) in third-line refractory mCRC.¹The FRESCO trial (NCT02314819) showed a median OS of 9.3 months with fruquintinib vs 6.57 months with placebo in mCRC (HR, 0.65; 95% CI, 0.51-0.83; P < .001).²

Lieu observed that OS hazard ratios were broadly similar between the studies, and participants agreed that patient characteristics and the safety and QOL profiles of the treatments would be highly influential in patient discussions and treatment selection.

Safety

Given the case patient’s low blood counts, some participants suggested fruquintinib to immediately address the myelosuppression. Incidence of myelosuppression was negligible in the FRESCO trial. In the SUNLIGHT trial, however, myelosuppression was reflected in grade 3 or higher hematologic adverse events (AEs), including neutropenia in 43.1% of patients in the trifluridine/tipiracil plus bevacizumab arm.¹ The rates of grade 3 or higher anemia and thrombocytopenia in this arm were 6.1% and 2.8%, respectively.¹

A participant noted that fruquintinib also offers a chemotherapy-free oral option providing patients with the logistical benefit of a break from receiving intravenous therapy at a clinic. While trifluridine/tipiracil is oral, bevacizumab requires infusion in a clinic.

When focusing on grade 3 or higher AEs beyond hematological, particularly cardiovascular or dermatological, trifluridine/tipiracil plus bevacizumab had a better safety profile than fruquintinib.

In the FRESCO trial, grade 3 or higher AEs in the fruquintinib arm included hypertension in 21.2% of patients and hand-foot skin reaction in 10.8%.² Further, grade ≥3 diarrhea occurred in 2.9% of these patients. The rates of these grade ≥3 AEs with trifluridine/tipiracil plus bevacizumab in the SUNRISE trial were 5.7%, <1%, and 0.8%, respectively.¹

Managing Myelosuppression

Attendees discussed practical approaches to managing cytopenias for those physicians choosing to use trifluridine/tipiracil plus bevacizumab in the third-line setting. Suggested options included extending intervals between cycles, dose reductions, and using growth factors.

Preserving Function

A recurring theme in the discussion was the importance of functional preservation in a population for whom OS gains are measured in months. Lieu presented data from a secondary analysis from the FRESCO-2 trial showing that time to ECOG performance status deterioration to 2 or greater, or death within 37 days of last dose, was 6.6 months in the fruquintinib arm vs 2.9 months in the placebo arm (HR, 0.551; 95% CI, 0.436-0.697; stratified P <.001).³ Comparable data from a secondary analysis of the SUNLIGHT trial showed that the time to ECOG performance status worsening was 9.3 months with trifluridine/tipiracil plus bevacizumab vs 6.3 months with trifluridine/tipiracil alone.⁴

QOL analyses from SUNLIGHT further demonstrated improvements in global health status, physical functioning, role functioning, and emotional functioning with the combination regimen.⁴

Attendees discussed the relative importance of QOL outcomes vs time to worsening ECOG performance status in terms of informing clinical decision-making. In general, the group considered both significant, with Lieu distinguishing the performance status metrics reflecting the physician’s assessment and QOL instruments as the patient’s assessment since the patients fill those out.

One participant argued that time to ECOG performance status worsening carries more objectivity, observing that QOL instruments are survey-driven and can be difficult to weigh. Another participant countered that patient-reported outcomes capture what the physician cannot observe directly: “What's more important, my perception of how a patient's doing, or theirs?” the attendee asked.

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DISCLOSURES: Lieu reported a consulting/advisory role with Amgen (Institution) and research support from Genentech (Institution).

REFERENCES

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

2. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855

3. Sobrero A, Dasari A, Aquino J, et al. Health-related quality of life associated with fruquintinib in patients with metastatic colorectal cancer: Results from the FRESCO-2 study. Eur J Cancer. 2025;218:115268. doi:10.1016/j.ejca.2025.115268

4. Taieb J, Fakih M, Tabernero J, et al. Impact of treatment with trifluridine/tipiracil in combination with bevacizumab on health-related quality of life and performance status in refractory metastatic colorectal cancer: an analysis of the phase III SUNLIGHT trial. Clin Colorectal Cancer. 2025;24(2):180-187.e4. doi:10.1016/j.clcc.2024.12.002