Third-Line Treatment Considerations for KRAS Wild-Type mCRC

Despite meaningful advances in the frontline and second-line management of metastatic colorectal cancer (mCRC), the third-line setting remains a challenge. The majority of patients do not have actionable alterations in BRAF, HER2, or mismatch repair, and consequently, their best available options produce modest response rates, limited disease control, and survival benefits measured in weeks rather than months. Against that backdrop, the question of how to sequence and select among approved agents demands careful consideration.

Christopher Lieu, MD, associate professor of medical oncology at the University of Colorado Anschutz Medical Campus, moderated a live Case-Based Roundtable event for community oncologists in Colorado. Lieu presented efficacy and safety data from the SUNLIGHT (NCT04737187),¹ FRESCO (NCT02264600),² FRESCO-2 (NCT04322539),³ and CORRECT (NCT01103323)⁴ trials, and led a detailed discussion of how practicing oncologists weigh those data in making decisions in the clinic.

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CASE SUMMARY

• A 58-year-old female teacher
• Diagnosed with mCRC 3 years ago
• Primary tumor: left-sided sigmoid
• Metastatic to liver and peritoneum
• Completely wild type: microsatellite stable, RAS/BRAF wild type, HER2 negative, low tumor mutational burden
• Medical history: type 2 diabetes, history of deep vein thrombosis
• Prior therapy: FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin)/bevacizumab (Avastin; frontline, 11 months) → FOLFIRI (leucovorin calcium, 5-fluorouracil, and irinotecan)/cetuximab (Erbitux; second line, 8 months before progression)
• Current status: grade 1 fatigue, grade 1 mild myelosuppression, ECOG performance status 1 (intermittently grade 2 for several days after chemotherapy cycles)
• Labs: white blood cells 3.2 × 10⁹/L, hemoglobin 10.2 g/dL, platelets 95 ×10⁹/L, alanine aminotransferase 65 U/L, aspartate aminotransferase 58 U/L

DISCUSSION QUESTION

• Based on the data discussed, how do the results from the SUNLIGHT, FRESCO, FRESCO-2, and CORRECT trials inform your approach to third-line therapy?

EVENT RECAP

Before reviewing the trial data, Lieu asked attendees to select their preferred third-line approach. A majority of the group (63.6%; 7 of 11) chose trifluridine/tipiracil (Lonsurf) plus bevacizumab (Avastin), with single votes for regorafenib (Stivarga), fruquintinib (Fruzaqla), trifluridine/tipiracil alone, and panitumumab (Vectibix) monotherapy. That initial preference set the stage for a conversation about whether the data support this selection and whether bevacizumab adds meaningful benefit in a patient who has already received it extensively during prior lines.

SUNLIGHT Trial: Trifluridine/Tipiracil Plus Bevacizumab in mCRC

The efficacy discussion centered on the phase 3 SUNLIGHT trial (NCT04737187), which randomly assigned patients with refractory mCRC 1:1 to trifluridine/tipiracil plus bevacizumab or trifluridine/tipiracil alone in the third-line setting. The result was a significant improvement in median OS: 10.8 months with the combination vs 7.5 months with trifluridine/tipiracil monotherapy (HR, 0.61; 95% CI, 0.49-0.77; P < .001).¹ The median progression-free survival (PFS) was 5.6 months vs 2.4 months (HR, 0.44; 95% CI, 0.36-0.54; P < .001).¹ Lieu noted that these results are among the most favorable PFS data seen in third-line mCRC to date.

Lieu said the OS benefit was observed across all patient subgroups. He then commented on the subgroup of approximately 30% of patients in SUNLIGHT who had not received prior bevacizumab. In that subgroup, the OS advantage was substantially larger—15.1 months vs 8.1 months (HR, 0.40). For patients who had received prior bevacizumab, the benefit narrowed but remained statistically significant, with a median OS of 9 months vs 7 months (HR, 0.72). Lieu acknowledged that “some of the overall trial efficacy is driven by the 30% of patients who had no prior bevacizumab,” while emphasizing that the benefit in the bevacizumab-exposed subgroup was still real and that the benefit in both populations was statistically significant.

The participants then further addressed this topic, discussing if a patient has been on bevacizumab throughout frontline and second-line treatment, is re-exposure alongside trifluridine/tipiracil actually adding anything? The discourse covered the scientific rationale for the approach, since re-engaging VEGF suppression in a new combination context may still confer angiogenic benefit, although acknowledging that the magnitude of that benefit in previously exposed patients is more modest than in bevacizumab-naive ones.

Assessing the Competing Third-Line Options

For context on the broader list of third-line options, Lieu reviewed FRESCO,² in which the VEGF-TKI fruquintinib 5 mg once daily produced a median OS of 9.3 months vs 6.6 months with placebo in patients who had progressed on at least 2 prior regimens (HR, 0.65; 95% CI, 0.55-0.77; P < .001). The global FRESCO-2 study³ extended this finding to a true fourth-line population of patients previously treated with trifluridine/tipiracil or regorafenib where fruquintinib produced a median OS of 7.4 months vs 4.8 months with placebo (HR, 0.66; 95% CI, 0.55-0.80; P < .0001) and median PFS of 3.7 months vs 1.8 months. In the CORRECT trial,⁴ regorafenib produced a median OS of 6.4 months vs 5.0 months with placebo (HR, 0.77; 95% CI, 0.64-0.94; P = .0052); although this study was first presented over a decade ago.

Lieu, while noting the inherent issues with cross-trial comparisons, said that looking at hazard ratios across SUNLIGHT, FRESCO, and FRESCO-2, the numbers are “all pretty similar,” whereas regorafenib's benefit of approximately 6 weeks of improvement in OS stood apart as the leftast compelling in this comparison. Across the trials, trifluridine/tipiracil had the best HR for OS at 0.61, as well as the highest median OS, median PFS, and disease control rate.

A Consensus Is Reached

After the group discussed all of the trial data, Lieu repeated the treatment preference question. The result was now an even greater preference for trifluridine/tipiracil at 87.5%. The poll reflected that that the SUNLIGHT OS and PFS data resonated with community oncologists, even accounting for the caveats around prior bevacizumab exposure.

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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. Dasari A, Lonardi S, Garcia-Carbonero R, et al. 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

4. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X