Reviewing Available Data to Decide Sequence of CRC Therapies

John L. Marshall, MD, director of the Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, and Marwan G. Fakih, MD, a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of Gastrointestinal Medical Oncology, and codirector of the Gastrointestinal Cancer Program at City of Hope, discussed the landscape and sequencing of treatment for refractory colorectal cancer.

TRANSCRIPTION:

0:06 | MARSHALL: Colon cancer is a very common disease. [Over] 50,000 people a year in the United States are going to have metastatic disease, and too many of those will die of their cancer. The ones [who] do die of their cancer are [part of] this refractory metastatic patient population. When we think about what that means, those are people who’ve already had oxaliplatin-based therapy, irinotecan-based therapy, [and] typically also any biologic [such as an] EGFR or VEGF inhibitor if they’re a candidate.

FAKIH: Historically speaking, before the SUNLIGHT trial [NCT04737187], we only had 2 options of therapy. One is trifluridine/tipiracil and the other one was regorafenib.

What we have seen in the last couple years is the approval of 2 additional treatments for refractory colorectal cancer. One is trifluridine/tipiracil/bevacizumab, and that's based on the randomized phase 3 clinical trial, the SUNLIGHT trial. And the other approval was for a tyrosine kinase inhibitor with significant activity against VEGF receptor 1, 2, and 3, and that is fruquintinib which is which was approved based on the FRESCO-2 trial [NCT04322539]. And so at this point, based on the NCCN guidelines, all these 4 treatment options are the treatment options for refractory colorectal cancer.

MARSHALL: For the most part, patients in the refractory metastatic setting are doing OK. They’ve already been undergoing treatment for 1 to 2 years. With cancer, we always worry about pain, organ dysfunction, and fatigue. We would like to have cancer shrink, but stable disease can be meaningful for these patients, so their needs are maintaining quality of life, maintaining function, and preventing progression of cancer.

FAKIH: The question is, without having randomized level 1 evidence, how do I sequence these drugs? I personally have to go with the data that is available to me. What I know is that trifluridine/[tipiracil]/bevacizumab has a median progression-free survival of 5.6 months, and I know that the median overall survival [OS] of those patients is 10.8 months.¹ Those are very good numbers for such a refractory patient population.

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 had prior trifluridine or had prior regorafenib. In that particular trial, the median OS was 7.4 months, which was better than placebo [or] no treatment.² The placebo group had a 4.8-month OS. So here you're seeing approximately 2.6 months’ improvement in OS, knowing that the FRESCO-2 data is in the fourth-line setting, and knowing that the overall outcomes numerically are lower than what we see with trifluridine/bevacizumab, I tend to use trifluridine/bevacizumab in my third-line treatment.

The counterapproach is that people would say the 7.4 months is in patients who are more heavily pretreated. But the reality is, we don't have data in the United States on fruquintinib in a strict third-line setting. We do have the FRESCO, which was done outside the US, and most of those patients were third-line patients, and median OS in that population was closer to the 9-months mark.³ So it's still not better than the 10.8 that we see with SUNLIGHT.

MARSHALL: You are always looking at…the next best chess move to play, and a lot depends on what you have played before. How much VEGF inhibition have you been giving? Has there been a break [in treatment] or not? Does the patient want to break from an intravenous treatment and only do oral therapies? What have the [adverse events] before been?

You want to not just have a routine…checkers-like approach to managing metastatic colon cancer. You want a chess-like approach, and you’re a better chess player if you look at what’s happened before and what you’ve got left ahead of you.

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. 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

3. 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

Image credit: CT colonography 3d rendering for screening colorectal cancer. Check up Screening cancer of colon. By samunella. Adobe id: 464574031.