Real-World Evidence Complements and Contextualizes Randomized Clinical Trial Insights in Colorectal Cancer

As data from prospective clinical trials continue to drive change and bring newer treatments to the colorectal cancer (CRC) realm, real-world evidence have helped further address unmet needs for patients who may be ineligible for clinical trials or descend from underrepresented populations.

Within the past decade, randomized clinical trial data have informed future research endeavors and sparked key drug development insights, including the rationale for combination strategies. For example, the phase 3 RECOURSE trial (NCT01607957) evaluated trifluridine and tipiracil (TAS-102; Lonsurf) compared with placebo for the treatment of patients with refractory metastatic CRC (mCRC).1 Data from the study showed that the median overall survival (OS) was 7.1 months (95% CI, 6.5-7.8) in the TAS-102 arm vs 5.3 months (95% CI, 4.6-6.0) in the placebo arm (HR, 0.68; 95% CI, 0.58-0.81). Furthermore, data from the study helped inform the phase 3 SUNLIGHT trial (NCT04737187), which assessed TAS-102 combined with bevacizumab (Avastin) compared with TAS-102 alone in patients with refractory mCRC.2 Data from the SUNLIGHT study revealed that the median OS was 10.8 months (95% CI, 9.4-11.8) vs 7.5 months (95% CI, 6.3-8.6) in the trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil alone arms, respectively.

“Randomized clinical trials are the gold standard of how…we inform our practice. It is essentially important in terms of understanding how new agents end up being [FDA-]approved and make their way to the clinic,” Tanios S. Bekaii-Saab, MD, said in an interview with OncLive®. “However, it is not [possible to answer] every question through a randomized clinical trial. We learn a lot from how we practice day-to-day, and the real-world evidence essentially tries to reflect our practice patterns. [Real-world data] essentially inform us on a lot of the questions that are impossible to ask in randomized clinical trials.”

Bekaii-Saab is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I at the Mayo Clinic College of Medicine and Science and the chairman of the Division of Hematology/Medical Oncology at the Mayo Clinic in Phoenix, Arizona.

The Synergy of Real-World Evidence and Clinical Trial Data in CRC

Head-to-head clinical trials are required for establishing treatments as standards of care (SOC), Bekaii-Saab noted; however, the designs of these studies can leave gaps. For example, although regorafenib (Stivarga), fruquintinib (Fruzaqla), and TAS-102 without bevacizumab have been compared with other SOCs in prospective studies, they have not been compared head-to-head vs each other in randomized clinical trials. Therefore, the 3 agents are considered equivalent regarding treatment decision-making in clinical practice, he explained. Nevertheless, data from real-world studies help clarify where differences lie and if there are differences in real-world practice from clinical practice, he emphasized.

In recent years, more real-world analyses have been conducted to identify whether sequencing strategies matter, Bekaii-Saab added. A retrospective study evaluated the efficacy and safety of regorafenib compared with TAS-102 in patients with chemotherapy-refractory mCRC using real-life clinical data, which revealed that factors such as tumor shrinkage, patient comorbidities, and toxicity profiles should be considered when selecting optimal treatment for patients.3 Results from the study demonstrated that no patients achieved complete or partial responses from the regorafenib or TAS-102 groups. Specifically, the median first progression-free survival (PFS) was 2.5 months (95% CI, 2.05-3.07) and 3.0 months (95% CI, 2.3-3.6) with regorafenib vs TAS-102, respectively (P = .25). The median first OS was 6.8 months (95% CI, 5.1-8.5) and 7.6 months (95% CI, 5.5-9.6) in the respective groups (P = .41). Of note, the findings showed that the optimal sequence of regorafenib and TAS-102 remains unknown.

“When I sit with my patients, I'm armed with 2 things: the randomized clinical trial to tell them this is a superior strategy vs not doing anything at this point, at least with survival,” Bekaii-Saab said. “Then, with the real-world evidence, I am empowered to sit with my patient and be able to discuss the different agents, their toxicities, and fall in line with the patient's preferences, understanding that some patients may have a desire not to be attached to an intravenous catheter anymore. They want to get an oral drug, take it home, and see me once a month or 2, and have a check with the pharmacist or with an advanced practice provider virtually and not have to come and see me.”

Additionally, both randomized clinical trial data and real-world study data are important in informing care for patients with CRC, especially those with microsatellite stable disease or who have KRAS mutations, according to Benjamin L. Schlechter, MD, a medical oncologist and senior physician in the Gastrointestinal Oncology Cancer Center at Dana-Farber Cancer Institute; as well as an assistant professor of Medicine at Harvard Medical School in Boston, Massachusetts.

“KRAS mutations define care in CRC, and we are entering an era of KRAS inhibitors, which is important,” he explained in a separate interview. “We have the FDA-approved KRAS G12C inhibitors, sotorasib [Lumakras] and adagrasib [Krazati], and hopefully soon, we'll have some combinations for KRAS G12C and other KRAS mutations.”

Real-world data presented at the 2025 ESMO Gastrointestinal Cancers Congress by Cathy Eng, MD, FACP, FASCO, and colleagues, demonstrated that outcomes were comparable among patients with KRAS G12C–mutated mCRC when treated with different first-line chemotherapy doublet regimens.4 However, patients with KRAS G12C–mutated mCRC experienced significantly shorter survival in the first-line setting compared with patients with KRAS mutations other than G12C. In particular, the median OS in patients with KRAS G12C mutations was 18.2 months (95% CI, 14.7-20.0) compared with 19.1 months (95% CI, 18.4-19.8) in patients with KRAS non-G12C mutations. Moreover, the real-world median PFS was 7.1 months (95% CI, 5.9-8.5) vs 8.9 months (95% CI, 8.4-9.2) in the KRAS G12C and non-G12C cohorts, respectively.

“We have 2 drugs that have already been FDA-approved specifically in the setting of the previously treated mCRC [with a KRAS G12C mutation]. However, we now have trials more specific to the KRAS G12C patient population. Therefore, as a provider, it entices me to try to obtain these drugs and participate in these clinical trials,” Eng said in an interview at the 2025 ESMO Gastrointestinal Cancers Congress. “For me, now that I know that there's a possibility it may affect the OS and the PFS for our patient population, rather than just giving them standard chemotherapy, why wouldn't I want to consider participation in a clinical trial specific to that patient, if they're eligible?”

Eng is the David H. Johnson Endowed Chair in Surgical and Medical Oncology; professor of Medicine, Hematology and Oncology; director of the Young Adults Cancers Program, and codirector of Gastrointestinal Oncology at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Addressing Unmet Needs With Real-World Evidence

Gaps in using treatments and regimens in clinical practice remain, even though randomized clinical trials have demonstrated they provide the highest level of evidence regarding the efficacy and safety of novel treatments and regimens prior to their use in clinical practice.5 The necessity of real-world evidence further answers clinical and policy-related questions that are not feasibly addressed in clinical trials. Of note, real-world evidence further complements findings from clinical trials by defining the efficacy of treatments in clinical practice and among patients who were excluded or underrepresented in clinical trials, describing the reliability and transferability of procedures, and further defining the safety of the treatment, especially with long-term adverse effects.

“[Randomized clinical trials] all seem to be relatively interchangeable at face value. Differences are primarily the toxicities, and efficacy is all very similar in the range, especially when we focus on survival, which is the ultimate end point,” Bekaii-Saab said. “Frankly, this is where we take our real-world evidence data and apply that standard to help us in practice. Therefore, there's a role for both [clinical trial data and real-world evidence], and it's essentially a role that allows us to use them complementarily, to inform practice.”

Although randomized clinical trial data can provide a basis for the efficacy and safety of treatments, real-world evidence takes it a step further by evaluating the efficacy and safety of treatments in underrepresented populations, including individuals with multiple comorbidities, pregnant individuals, and older adults.6

“Most patients we treat, whether in academic centers or community [centers], are not [always] included in clinical trials. They're less selected, and sometimes they tend to be older…or come from rural areas and may not be able to afford to come multiple times to the clinic,” Bekaii-Saab noted.

Furthermore, patients who are underrepresented in clinical trials could respond to treatments differently. For instance, when patients with mCRC are given regorafenib or fruquintinib at fixed doses, Asian patients—who commonly have a lower body surface area compared with White patients—could experience more toxicities to treatment, Bekaii-Saab explained.

Still, changes in the way clinical trials build inclusive and exclusive criteria matter, to ultimately continue getting treatments FDA-approved and thus moved into clinical practice, Schlechter and Eng emphasized.

“In the past, we've depended on the cooperative groups of the National Institutes of Health and the National Cancer Institute to do trials. Obviously, there are a lot of concerns about that right now with data collection and who we're collecting on,” Schlecter added. “Are we allowed to make distinctions on race and ethnicity, which are real differences in how patients [respond to treatment? They're [likely] not biological differences; there are sociological differences. However, we need to study them. We should, as an oncology community, focus on clinical trial designs that are practical and inform practice, and we need to disseminate them so that everyone adopts these practices quickly.”

“We want to encourage patients as much as possible to participate in clinical trials—it's of key importance. That's how we move the needle forward, and unless we have those patients who participate in trials, it takes so much longer to make progress and continue to see what's available to them,” Eng said. “They should continue to ask great questions of their treating physician and consider being treated outside the box and not just receiving the SOC.”

References

1. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi:10.1056/NEJMoa1414325
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. Vitale P, Zanaletti N, Famiglietti V, et al. Retrospective study of regorafenib versus tas-102 efficacy and safety in chemorefractory metastatic colorectal cancer (mCRC) patients: a multi-institution real life clinical data. Clin Colorectal Cancer. 2021;20(3):227-235. doi:10.1016/j.clcc.2021.06.002
4. Eng C, Fakih MG, Halil Sahin I, et al. Real world first-line treatment outcomes of patients with KRAS G12C-or non-G12C KRAS mutated metastatic colorectal cancer in the US. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 46P.
5. Di Maio M, Perrone F, Conte P. Real-world evidence in oncology: opportunities and limitations. Oncologist. 2020;25(5):e746-e752. doi:10.1634/theoncologist.2019-0647
6. Costa V, Custodio MG, Gefen E, Fregni F. The relevance of the real-world evidence in research, clinical, and regulatory decision making. Front Public Health. 2025;13:1512429. Published 2025 Feb 18. doi:10.3389/fpubh.2025.1512429