Illuminating the Sequence of Third-Line Therapies in Metastatic CRC

Treatment beyond initial chemotherapy for advanced or metastatic colorectal cancer (mCRC) is a challenging field with few positive options. During a Case-Based Roundtable event in Miami, Florida, Christine M. Parseghian, MD, led a discussion on the evolving treatment landscape for mCRC. Parseghian, associate professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, presented clinical data supporting second and subsequent lines of therapy. By reviewing the case of a 58-year-old patient with refractory disease, she highlighted key findings from several trials to illustrate how recent advancements are shaping sequencing strategies in the third-line setting and beyond.

CASE SUMMARY

• A 58-year-old female teacher was diagnosed with mCRC 3 years ago. The primary tumor was in the sigmoid colon with metastatic lesions in the liver and peritoneal implants.
• Tumor genomics: microsatellite stable, RAS wild type, BRAF wild type, HER2-negative, low tumor mutational burden ​
• Medical history: controlled hypertension, type 2 diabetes and history of deep vein thrombosis 5 years ago​
• She received FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) plus bevacizumab (Avastin) in the first line with initial partial response; progression after 11 months of therapy.
  • During treatment she experienced grade 2 peripheral neuropathy which stabilized with oxaliplatin dose reduction.​
• She received FOLFIRI (leucovorin calcium, 5-fluorouracil, and irinotecan) plus cetuximab (Erbitux) in the second line with initial disease control; progression after 8 months of therapy.
  • She experienced grade 1 skin rash that was managed with topical treatments.
• Currently, she reports grade 1 fatigue that worsens toward the end of each treatment cycle and grade 1 myelosuppression.
• Last imaging showed mixed response with no new lesions.​
• ECOG status of 1 (intermittently grade 2 for serval days after each chemotherapy cycle)​
• Laboratory findings:
• 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​

Targeted Oncology: What are the NCCN guidelines for advanced/metastatic colon cancer for second and subsequent lines?

Christine M. Parseghian, MD: [Looking at] the second line or subsequent therapy options for metastatic disease, if they had previous oxaliplatin [without irinotecan], we all are familiar with [using] irinotecan-based regimens.¹ If they are RAS/BRAF wild type, and they haven’t had the anti-EGFR, go ahead and give the anti-EGFR, just like what we did with this patient. If they have had oxaliplatin and irinotecan, there is the option to give anti-EGFR here. This would be essentially in the third-line setting. These 3 options exist: fruquintinib [Fruzaqla], regorafenib [Stivarga], and trifluridine/tipiracil [Lonsurf] with or without bevacizumab, with bevacizumab now being the preferred combination [by] NCCN. [Another option is] best supportive care.

If they have a targetable tumor, then you could do BRAF-targeted therapy, [or] you could do HER2-amplified therapy with trastuzumab [Herceptin] and tucatinib [Tukysa] or pertuzumab [Perjeta]. If they’re HER2 amplified [by immunohistochemistry] 3+, you could use trastuzumab deruxtecan [Enhertu]. For the [KRAS] G12C-positive patients, we have 2 options, sotorasib [Lumakras] or adagrasib [Krazati], and cetuximab or panitumumab [Vectibix]. There are targeted agents for NTRK fusions and RET fusions.

CASE UPDATE

• The patient received trifluridine/tipiracil plus bevacizumab as third-line therapy; is currently on month 4 of treatment.​

What data support the use of trifluridine/tipiracil plus bevacizumab?

My personal use of this [regimen] comes from the phase 3 SUNLIGHT trial [NCT04737187].² This was a phase 3 randomized controlled trial for patients with 2 prior regimens and disease progression or intolerance. They were randomly assigned 1:1 to trifluridine/tipiracil plus bevacizumab vs trifluridine/tipiracil, and they followed up every 8 weeks for radiologic progression and survival. The responses were significantly different. The HR for death was 0.61 [95% CI, 0.49-0.77; P < .001]. The trifluridine/tipiracil and bevacizumab combination resulted in a median overall survival [OS] of nearly 11 months, compared with about 7.5 months with trifluridine/tipiracil alone. By subgroup analysis, despite RAS status, mutated or wild type, these patients [had similar outcomes]. Often, these RAS-mutated patients have a much poorer prognosis and don’t have as many options. But in this patient population, they did pretty similarly in the SUNLIGHT trial [HR of 0.62 with RAS mutant and 0.64 for RAS wild type].

In terms of progression-free survival [PFS], the HR was 0.44 [95% CI, 0.36-0.54; P < .001]. The median PFS was about 5.5 months with the trifluridine/tipiracil/bevacizumab combination vs just about 2.5 months in the trifluridine/tipiracil alone arm. Looking at subgroups as well, there was a little bit of a difference that we saw here in the RAS mutated [HR, 0.51] vs the wild type setting [HR, 0.29], but overall, again, that hazard ratio of 0.44 was pretty dramatic for the third line.

What is the evidence for using regorafenib?

The CORRECT trial [NCT01103323] is the regorafenib vs placebo trial.³ This is now very old, but essentially, patients who had progression on at least 2 lines of therapy were randomly assigned 2:1 to regorafenib and best supportive care vs placebo and best supportive care. Their primary end point was OS, and regorafenib had a [median OS of] 6.4 months vs 5 months with placebo. The HR here was 0.77 [95% CI, 0.64-0.94; P = .00052]. In 2013, they were excited by this, [but] we’re not so excited anymore. At the time, [there were] limited options, and this dose is the 160 [mg once daily] and that 160 mg is pretty difficult to tolerate. I can’t remember the last time I prescribed regorafenib…but when we do, our departments’ criteria is starting at 80 mg. The response rates are probably lower [with that dose]. Also, in the [Kaplan-Meier curves for OS], the lines cross [at 12 months]. The PFS HR is 0.49 [95% CI, 0.42-0.58; P < .0001], a little bit of a difference here, but again, not profound.

What stands out about the data for using fruquintinib?

This is where it gets a little bit more interesting. The phase 3 FRESCO study [NCT02314819] had patients with 2 or more lines of therapy randomly assigned 2:1 to fruquintinib vs placebo, and essentially continued until progressive disease.⁴ Interestingly, 70% of these patients were bevacizumab naive, an interesting take-home from the first FRESCO study. There was a median OS of 9 months compared with placebo, which is about 6.5 months. That was a very nice difference with the HR of 0.65 [95% CI, 0.51-0.83; P < .001]. There was PFS benefit as well, [a median of] 3.7 vs 1.8 months, [which is] not very exciting, but better than placebo [HR, 0.26; 95% CI, 0.21-0.34; P < .001].

But this led to the phase 3 FRESCO-2 study [NCT04322539].⁵ In my opinion, this is of greater interest. This [enrolled] patients [whose disease was] very refractory. They progressed on FOLFOX, FOLFIRI, and anti EGFR if they were BRAF/RAS wild type. Here, they [must have] progressed on either trifluridine/tipiracil or regorafenib. These patients were randomly assigned to 2:1 to fruquintinib vs placebo here as well. Despite being so heavily refractory, in these patients, the median OS was 7.4 months compared with the placebo of 4.8 months, and that was their primary end point. In terms of the PFS for the fruquintinib group, it was 3.7 months compared with a placebo group of 1.8 months.

FRESCO-2 is nice because it gave us the data of patients who had either trifluridine/tipiracil or regorafenib, [followed by] fruquintinib. They did very nicely, despite the prior history of the trifluridine/tipiracil. I think this tells me at least in my practice that if I [give] trifluridine/tipiracil first, I have fruquintinib in my fourth-line setting, because I know that it will give me an OS of 7.4 months, whereas there are no great data for regorafenib in the fourth-line setting.You could do it, but at that point, at the time you see a fourth-line patient with CRC, they [have poor performance status] already. My practice is going SUNLIGHT and then FRESCO….

DISCLOSURES: Parseghian had no known relevant disclosures.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 5.2025. Accessed December 17, 2025. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf

2. 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

3. 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-

4. 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

5. 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