Third-Line mCRC: Balancing Efficacy, Toxicity, and Quality of Life

When patients with metastatic colorectal cancer (mCRC) reach the third-line setting, care shifts toward managing cumulative toxicities and revisiting what quality of life means to each patient, according to Christine Poblete, MSN, APRN, FNP-BC, a family nurse practitioner in hematology/oncology at Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, in Dallas, Texas.

Poblete moderated an Oncology Nursing News Case-Based Roundtable event held October 15, 2026, in Minneapolis, Minnesota, where oncology nurses and advanced practice providers discussed later-line therapy.

Which third-line options did the roundtable review?

For mismatch repair–proficient or microsatellite-stable disease, National Comprehensive Cancer Network guidelines list trifluridine/tipiracil (Lonsurf) with or without bevacizumab (Avastin), fruquintinib (Fruzaqla), and regorafenib (Stivarga).¹ The group reviewed each regimen's pivotal trial:

• SUNLIGHT (NCT04737187): Trifluridine/tipiracil plus bevacizumab improved median overall survival (OS) vs trifluridine/tipiracil alone (10.8 vs 7.5 months; HR, 0.61; 95% CI, 0.49-0.77; P < .001).²
• FRESCO-2 (NCT04322539): Fruquintinib improved median OS vs placebo (7.4 vs 4.8 months; HR, 0.66; 95% CI, 0.55-0.80; P < .0001).³
• CORRECT (NCT01103323): Regorafenib improved median OS vs placebo (6.4 vs 5.0 months; HR, 0.77; 95% CI, 0.64-0.94; P = .0052).⁴

Participants noted that all 3 trials enrolled patients with an ECOG performance status of 0 to 1, which may not reflect patients seen in clinic. "Lots of times when our patients are on third line settings, they're either in the hospital at least once a month, unfortunately," Poblete said. In a live poll, 63% of attendees said trifluridine/tipiracil plus bevacizumab was the regimen used most often in their practice. A previous Oncology Nursing News roundtable examined how real-world outcomes compare with these trial benchmarks.⁵

Which adverse events are hardest to manage in later lines?

In polling, 70% of attendees called adverse event (AE) management the biggest barrier to optimizing third-line therapy, naming fatigue (39.3%), myelosuppression (21.4%), and hypertension (17.9%) as the most challenging AEs.

In SUNLIGHT, grade 3 or higher neutropenia occurred in 43.1% of patients receiving the combination vs 32.1% of those receiving trifluridine/tipiracil alone.² Grade 3 or higher hypertension occurred in 14% of patients receiving fruquintinib in FRESCO-2,³ and grade 3 or higher hand-foot skin reaction in 17% of those receiving regorafenib in CORRECT.⁴

Poblete described relying on pharmacists for growth factor support. "A lot of times patients are like, 'What is this?' Right, they have to give it themselves at home," she said, noting that self-injection can become "another kind of barrier in regards to adherence too."

How are dose decisions made in practice?

In one case, a patient receiving trifluridine/tipiracil plus bevacizumab with easy bruising and a platelet count of 45,000/mm³ had her next dose delayed; platelets recovered to 80,000/mm³ after 5 days. In another, a patient with atrial fibrillation developed grade 3 hand-foot skin reaction and grade 2 hypertension on fruquintinib; participants agreed they would hold the dose and reduce from 5 mg to 4 mg as blood pressure is controlled.

In a poll, 54.5% of attendees said dosing changes were a shared decision. "I see that my physician slowly tapers off when you know that that patient may not do so well with that full dose yet," Poblete said. "So that's always a collaborative effort."

How can nurses keep goals-of-care conversations going?

"Everyone's a little bit different how they tolerated treatments prior, but it's a conversation of…what's important to them, what does quality of life look like to them, what side effects worry them now that we're here in this moment," Poblete said.

Those conversations should be revisited, she added: "Sometimes we just like keep going, we're so used to routine, but then sometimes we just have to pause and be like, 'Hey, how are you doing?'"

The group also reviewed real-world data showing that treatment duration with trifluridine/tipiracil plus bevacizumab was similar in patients with an ECOG performance status of 2 vs 0 to 1 (3.3 vs 3.6 months; P = .10), although median OS was shorter (6.8 vs 9.8 months; P < .01).⁶

What is on the horizon?

In the phase 3 STELLAR-303 trial (NCT05425940), zanzalintinib plus atezolizumab (Tecentriq) improved median OS vs regorafenib (10.9 vs 9.4 months; HR, 0.80; 95% CI, 0.69-0.93; P = .0045).^7,8 The FDA has set a target action date of March 3, 2027, for the combination.⁸

What are the key takeaways for oncology nurses?

• Anticipate myelosuppression, particularly with trifluridine/tipiracil plus bevacizumab.
• Monitor blood pressure and skin closely with fruquintinib or regorafenib.
• Coordinate dose holds and reductions with physicians and pharmacists.
• Revisit goals of care regularly, not only when therapy changes.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 2.2026. Accessed October 23, 2026. 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. 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

5. Navigating efficacy benchmarks and real-world outcomes in metastatic colorectal cancer. Oncology Nursing News. May 28, 2026. Accessed October 23, 2026. https://www.oncnursingnews.com/view/navigating-efficacy-benchmarks-and-real-world-outcomes-in-metastatic-colorectal-cancer

6. Nusrat M, Zhao R, He Y, et al. Clinical outcomes of patients with metastatic colorectal cancer treated with trifluridine-tipiracil + bevacizumab by performance status. JCO Oncol Adv. 2026;3:e2500174. doi:10.1200/OA-25-00174

7. Hecht JR, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial. Lancet. 2025;406:2360-2370. doi:10.1016/S0140-6736(25)02025-2

8. FDA delays decision on zanzalintinib combo for mCRC. Targeted Oncology. September 11, 2026. Accessed October 23, 2026. https://www.targetedonc.com/view/fda-delays-decision-on-zanzalintinib-combo-for-mcrc