Patients with metastatic colorectal cancer (mCRC) who progress through 2 prior lines of therapy face a narrowing therapeutic window—and a growing body of evidence is helping nurses, advanced practice providers (APPs), and physician assistants (Pas) make better-informed decisions about which agents to reach for next.
At a recent case-based roundtable, Julie Elliott, MS, PA-C, a physician assistant in oncology at Rocky Mountain Cancer Centers, reviewed clinical trial data, compared efficacy across third-line regimens, and discussed how real-world outcomes align—or diverge—from what the pivotal trials showed.
What should providers know about current third-line treatment options in mCRC?
The NCCN Guidelines1 outline several options for patients with proficient mismatch repair/ microsatellite stable (pMMR/MSS) mCRC who have progressed on or are ineligible for checkpoint inhibitor immunotherapy. For those who have received both oxaliplatin- and irinotecan-based regimens, the guideline-recommended options include trifluridine/tipiracil (FTD/TPI; Lonsurf) with or without bevacizumab (Avastin), fruquintinib (Fruzaqla), and regorafenib (Stivarga), along with tumor-agnostic and HER2-directed therapies for select molecular profiles.
Elliott’s roundtable zeroed in on the 4 regimens supported by the largest phase 3 datasets.
The SUNLIGHT trial (NCT04737187)2 enrolled 492 patients with mCRC who had progressed after at least 2 prior regimens. Patients were randomized 1:1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab (5 mg/kg IV on days 1 and 15 of a 28-day cycle). The combination arm delivered a median overall survival (OS) of 10.8 months compared with 7.5 months for FTD/TPI alone (HR, 0.61; 95% CI, 0.49–0.77; P < .001). Median progression-free survival (PFS) nearly tripled in the combination arm — 5.6 months vs 2.4 months (HR, 0.44; 95% CI, 0.36–0.54; P < .001) — and the disease control rate (DCR) reached 76.6%.
The phase 3 FRESCO trial (NCT02314819)3 tested fruquintinib 5 mg orally once daily (3 weeks on, 1 week off) vs placebo plus best supportive care in a Chinese patient population. Among 416 patients, fruquintinib yielded a median OS of 9.3 months vs 6.6 months for placebo (HR, 0.66; 95% CI, 0.52–0.85; P = .001) and a median PFS of 3.7 months vs 1.8 months (HR, 0.26; 95% CI, 0.21–0.34; P < .001), with a DCR of 62.2%.
The FRESCO-2 trial (NCT04322539)4 brought fruquintinib to a global population that had also progressed on or been intolerant to TAS-102 and/or regorafenib. Among 691 patients, fruquintinib achieved a median OS of 7.4 months vs 4.8 months for placebo (HR, 0.66; 95% CI, 0.55–0.80; P < .0001) and a median PFS of 3.7 months vs 1.8 months (HR, 0.32; 95% CI, 0.27–0.39; P < .0001).
The oldest dataset in the comparison, the CORRECT trial (NCT01103323)5 randomized 760 patients with refractory mCRC 2:1 to regorafenib 160 mg orally once daily or placebo plus best supportive care. Regorafenib extended median OS to 6.4 months vs 5.0 months (HR, 0.77; 95% CI, 0.64–0.94; P = .0052) and median PFS to 1.9 months vs 1.7 months (HR, 0.49; 95% CI, 0.42–0.58; P < .0001), with a DCR of 41%.
Across all four trials, FTD/TPI plus bevacizumab demonstrated the longest median OS (10.8 months) and highest DCR (76.6%), though the panel noted the importance of recognizing differences in patient populations and comparator arms when drawing cross-trial comparisons.
What do the real-world outcomes data show?
One of the discussions centered on whether trial efficacy translates to everyday practice. Real-world studies largely validated the SUNLIGHT findings—and in some cases, extended them.
A retrospective Texas Oncology study6 of 265 patients found a median OS of 11.6 months for those receiving FTD/TPI plus bevacizumab, vs 6.2 months for FTD/TPI alone. A larger ConcertAI RWD360 analysis7-8 of 3,680 patients confirmed a median OS of 8.9 months for the combination vs 5.8 months for monotherapy after propensity score matching (HR, 0.68; P.0001).
Importantly, a separate ConcertAI analysis9 focusing on Black patients with mCRC (n = 639) showed a median OS of 10.8 months with FTD/TPI plus bevacizumab vs 6.2 months for FTD/TPI alone (HR, 0.45; 95% CI, 0.33–0.63; P < .0001)—a finding panelists called particularly meaningful given the underrepresentation of Black patients in clinical trials and the documented disparities in CRC outcomes.
Real-world data for fruquintinib—drawn from 2 retrospective multicenter studies10-11—showed median OS of 5.0 to 7.2 months depending on line of therapy, tracking modestly below the FRESCO trial but broadly consistent with FRESCO-2 global population findings.
Nursing Takeaways
- FTD/TPI plus bevacizumab has the most robust efficacy datasetacross clinical trial and real-world settings, with benefit observed regardless of race and in patients with PS 2 in real-world practice.
- Cross-trial comparisons require caution: differences in patient populations, prior therapy requirements, and comparator arms limit direct head-to-head interpretation.
- Real-world evidence increasingly supports guideline-recommended approaches and can inform conversations with patients about what to expect from treatment.
- Molecular profiling remains essential: Patients with KRAS G12C mutations, HER2 overexpression, NTRK fusions, or RET fusions have targeted options that should be identified early and revisited at progression.
What is an emerging treatment option for third-line metastatic CRC?
The roundtable also touched on the STELLAR-303 trial (NCT05425940)12, presented at ESMO 2025, which evaluated the combination of zanzalintinib (a multi-kinase inhibitor) 100 mg orally once daily plus atezolizumab (Tecentriq) 1200 mg IV every 3 weeks vs regorafenib in patients with non-MSI-H/non-dMMR mCRC. With 901 patients enrolled, the trial measured OS in the intent-to-treat population and in the subgroup with liver metastases as co-primary endpoints.
While panelists noted the data remains investigational, the emergence of combination immunotherapy/tyrosine kinase inhibitor strategies reflects the continued push to improve outcomes in a population where median survival remains under 1 year.
References
- NCCN Guidelines. Rectal Cancer Version 2.2026. NCCN Guidelines Colon Cancer Version 2.2026. Accessed May 28, 2026.
- Prager GW, Taieb J, Fakih M, et al. Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023;388:1657-1667.
- 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.
- 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.
- 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):303-12.
- Richards DA, Zhao R, Khan N, Chang B, Mahmud S, Salimi T. Real-world treatment patterns and outcomes with trifluridine/tipiracil monotherapy or in combination with bevacizumab in metastatic colorectal cancer. JCO. 2025;43:3580-3580.
- Nusrat M, Zhao R, Khan N, et al. Real-world clinical outcomes of patients (Pts) with metastatic colorectal cancer (mCRC) who received trifluridine-tipiracil (FTD-TPI) monotherapy or FTD-TPI + bevacizumab (FTD-TPI+bev) combination therapy. JCO. 2025;43:79-79.
- Nusrat M, Zhao R, Khan N, et al. Trifluridine-Tipiracil with and without Bevacizumab in Colorectal Cancer. NEJM Evid. 2026;5(3):EVIDoa2500120.
- Nusrat M, Zhao R, Khan N, et al. Real-world clinical outcomes of trifluridine-tipiracil monotherapy (FTD-TPI) and FTD-TPI + bevacizumab combination therapy (FTD-TPI+bev) in 639 black patients (pts) with metastatic colorectal cancer (mCRC). JCO. 2025;43:81-81.
- Bansal V. Real-world use of fruquintinib in refractory metastatic colorectal cancer in the United States. J Clin Oncol. 2025;43(16).
- Abidoye O, Peersen A, Bauernfeind J, et al. Real-world evidence of fruquintinib (Fruq) efficacy after regorafenib (Rego) and trifluridine–tipiracil (TAS-102) in refractory metastatic colorectal cancer (mCRC). J Clin Oncol. 2025;43(16):supple.e23317.
- Saeed A, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab (zanza + atezo) vs regorafenib (rego) in patients (pts) with previously treated metastatic colorectal cancer (mCRC): Primary overall survival (OS) analysis from the randomized, open-label, phase III STELLAR-303 study. Ann Oncol. 2025;36:supplement 2S1574-S1575. Abstract LBA30.
