SUNLIGHT Trial Defines CRC in the Refractory Setting

3D rendering of GI tract - stock.adobe.com

The role of precision medicine in advanced colorectal cancer (CRC) has made significant inroads. Although standard regimens that involve a combination of surgery, chemotherapy, and targeted and immunotherapies have demonstrated beneficial outcomes, once patients become refractory to them, the treatment options are limited. Historically, before the emergence of data from the SUNLIGHT trial (NCT04737187),¹ there were only 2 options of therapy: trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga).

But in the past few years, in the refractory metastatic CRC setting, the approvals of the combination of trifluridine/tipiracil plus bevacizumab (Avastin) and fruquintinib (Fruzaqla) have been encouraging.^2-4

Targeted Therapies in Oncology interviewed Marwan G. Fakih, MD, a professor in the Department of Medical Oncology and Therapeutics Research and an associate director for clinical sciences at City of Hope in Duarte, California, about the current treatment landscape in refractory metastatic CRC.

Targeted Therapies in Oncology (TTO): What is the current treatment landscape? Could you describe the SUNLIGHT study in more detail?

Marwan G. Fakih, MD: The landscape is changing, but it is still important to note that targeted options can only be used in less than 5% to 6% of the patient population. About 95% of the patients we are treating are not based on a biomarker because there’s no driver or biomarker that can be targeted at this point. Beyond the standard regimens, we now have 2 additional treatment options based on findings from the SUNLIGHT trial and the FRESCO-2 trial [NCT04322539].

SUNLIGHT investigators reported that the median overall survival [OS] was 10.8 months in the trifluridine/tipiracil plus bevacizumab group and 7.5 months in the trifluridine/tipiracil only group [HR, 0.61; 95% CI, 0.49-0.77; P < .001].¹ The median progression-free survival [PFS] was 5.6 months in the combination group and 2.4 months in the control group [HR, 0.44; 95% CI, 0.36-0.54; P < .001].¹

The investigators reported that adding bevacizumab to trifluridine/tipiracil improved [OS] by more than 3 months in this refractory patient population.

[Although] it took a median of 2.4 months for the patients who received trifluridine/tipiracil to progress, that median PFS was 5.6 months. That results in more than doubling of the median [PFS]. I think the data were remarkable in that [they] showed a meaningful clinical impact on the outcome of patients with advanced metastatic [CRC] in the third-line setting based on the improvement in PFS and, more importantly, the benefit in OS of patients.

Although these treatments are biomarker agnostic, we have seen [additional treatment options] over the past 2 or 3 years…such as those for HER2-amplified colon cancer. Those patients can now receive tucatinib [Tukysa] plus trastuzumab [Herceptin].⁵ We also have KRAS G12C inhibitors— adagrasib [Krazati] in combination with cetuximab [Erbitux]—that are FDA approved.⁶

What is the rationale for the SUNLIGHT trial?

The rationale for the SUNLIGHT trial is that we have consistently observed the continuation of an angiogenesis targeting agent across lines of treatment in metastatic CRC, resulting in an improvement in outcomes.

Specifically, according to findings from the phase 3 TML study,⁷ continuing bevacizumab beyond first-line progression in the second- line setting with chemotherapy prolongs OS and PFS. The same had been shown for ramucirumab [Cyramza] and aflibercept [Zaltrap] in the second-line setting despite prior progression on bevacizumab in the first-line setting.

The hypothesis is if you continue suppressing angiogenesis across lines of therapy, you may improve outcome. This led to the testing of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil alone.

Are there any factors that affect treatment selection for this combination? Is there a patient population that benefits more than another with the addition of bevacizumab?

No; everyone benefits. However, it is true that certain patient characteristics are associated with a worse outcome, but that applies to both arms of the treatment, whether it’s trifluridine/tipiracil or trifluridine/tipiracil plus bevacizumab.

For example, patients without liver metastases did better [in both] arms…than the patients with liver metastases. But whether a patient has liver metastases or not, the addition of bevacizumab improved the outcome.

Does prior use of bevacizumab affect the outcome?

Yes, it does, in that patients who were bevacizumab naive when they enrolled in the study had a better OS in both arms, and they had a better outcome than patients who had prior bevacizumab. Naturally, those patients are less resistant to treatment. But whether they had prior bevacizumab or not, the addition of bevacizumab to trifluridine/tipiracil improved the overall outcome. So, across the board, we did not find any subgroup of patients who did not benefit from adding bevacizumab. All subgroups benefited from adding bevacizumab.

How do you approach sequencing the combination with other approved regimens?

Although we don’t have randomized level 1 evidence, we have to go with the data that are available.

What I know is that trifluridine/tipiracil plus bevacizumab has a median PFS of 5.6 months, and I know that median OS of those patients is 10.8 months. Those are good numbers for a refractory patient population.

I think the FRESCO-2 trial that led to the approval of fruquintinib was conducted as more of a fourth-line study, and it included patients who had either prior trifluridine/tipiracil or prior regorafenib.

In that particular trial, the median [OS] was 7.4 months, which was better than placebo. The placebo group had a 4.8-month OS. Here, you’re seeing an improvement of about 2.6 months in survival. Knowing that the FRESCO-2 data are in the fourth-line setting and that the overall outcomes are numerically lower than what we see with trifluridine/ tipiracil plus bevacizumab, I tend to use trifluridine/tipiracil plus bevacizumab in my third-line treatment.

The counterargument is that the 7.4 months observed in FRESCO-2 is seen in patients who are more heavily pretreated [than in SUNLIGHT]. But the reality is we don’t have data in the United States on fruquintinib in the third-line setting.

We do have [results from] the FRESCO trial [NCT02314819],⁸ which was conducted outside the US. Most of those patients were in the third-line setting, and the [OS] in that population was closer to the 9-month mark. So, it’s still not better than the 10.8 months that we see with the SUNLIGHT trial. Although there are a lot of caveats and comparing apples to oranges [is not ideal], one has to make a decision.

In my clinical experience, trifluridine/tipiracil plus bevacizumab is well tolerated by patients. Patients do develop neutropenia, but it’s asymptomatic, and you can control it with growth factors.

I would rather err on the higher absolute numbers that we have seen in the SUNLIGHT trial, and unless there’s a contraindication using trifluridine/tipiracil plus bevacizumab, that is typically my third-line treatment. I would use fruquintinib in the fourth-line setting at this point, because I do think the FRESCO-2 data are compelling.

The median PFS in that study was approximately 3.7 months, so you can still control the disease in a fair number of patients. Although it’s not a head-to-head study, it’s still better than historically described regorafenib.

Are there any unanswered questions that you’d like to see explored in the refractory disease setting?

Yes, absolutely. I think there is still a role for immunotherapy, and it has to be defined better. I think there’s room for novel RAS inhibitors and antibody-drug conjugates. We definitely need more novel agents for refractory disease. I would encourage community oncologists to be on the lookout for clinical trials to improve outcomes.

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. FDA approves trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer. FDA. August 2, 2023. Accessed March 26, 2025. https://tinyurl.com/wjbawf5b

3. FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2023. Accessed March 26, 2025. https://tinyurl.com/57x69j9s

4. 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

5. Casak SJ, Horiba MN, Yuan M, et al. FDA approval summary: tucatinib with trastuzumab for advanced unresectable or metastatic, chemotherapy refractory, HER2-positive RAS wild-type colorectal cancer. Clin Cancer Res. 2023;29(21):4326-4330. doi:10.1158/1078-0432.CCR-23-1041

6. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed March 26, 2025. https://tinyurl.com/2ks37xke

7. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). J Clin Oncol. 2012;30(suppl 15):3503. doi:10.1200/jco.2012.30.15_suppl.cra3503

8. 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