Real-world evidence is increasingly filling critical gaps left by randomized clinical trials in colorectal cancer (CRC) treatment, providing insights for patient populations typically excluded from clinical studies and informing treatment sequencing decisions that trials cannot address.
While randomized clinical trials remain the gold standard for drug approval and establishing standards of care, their rigid designs often leave practical questions unanswered, according to leading oncologists. "Randomized clinical trials are the gold standard of how we inform our practice," said Tanios S. Bekaii-Saab, MD, chairman of the Division of Hematology/Medical Oncology at the Mayo Clinic in Phoenix, Arizona. "However, it is not possible to answer every question through a randomized clinical trial."
Treatment Sequencing Challenges Persist
A key area where real-world evidence provides value is in treatment sequencing decisions. Although regorafenib (Stivarga), fruquintinib (Fruzaqla), and TAS-102 without bevacizumab have been compared with other standards of care in prospective studies, they have not been compared head-to-head in randomized clinical trials. This leaves the three agents considered equivalent in treatment decision-making, creating uncertainty for clinicians.
A retrospective study evaluating regorafenib compared with TAS-102 in patients with chemotherapy-refractory metastatic CRC using real-world data revealed important considerations. The study showed median first progression-free survival was 2.5 months (95% CI, 2.05-3.07) with regorafenib versus 3.0 months (95% CI, 2.3-3.6) with TAS-102 (P = .25). Median first overall survival 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). Notably, the optimal sequence of these agents remains unknown.
KRAS G12C Mutations Show Distinct Outcomes
Real-world data presented at the 2025 ESMO Gastrointestinal Cancers Congress revealed significant differences in outcomes for patients with KRAS G12C-mutated metastatic CRC. Patients with KRAS G12C mutations experienced shorter survival compared to those with other KRAS mutations, with median overall survival of 18.2 months (95% CI, 14.7-20.0) versus 19.1 months (95% CI, 18.4-19.8) for KRAS non-G12C mutations.
The real-world median progression-free survival was also shorter at 7.1 months (95% CI, 5.9-8.5) versus 8.9 months (95% CI, 8.4-9.2) in the KRAS G12C and non-G12C cohorts, respectively. These findings have implications for treatment planning, particularly as FDA-approved KRAS G12C inhibitors sotorasib (Lumakras) and adagrasib (Krazati) become available.
"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?" said Cathy Eng, MD, codirector of Gastrointestinal Oncology at Vanderbilt-Ingram Cancer Center.
Addressing Underrepresented Populations
Real-world evidence proves particularly valuable for understanding treatment effects in populations typically excluded from clinical trials. "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," Bekaii-Saab noted.
These underrepresented populations may respond differently to treatments. For instance, Asian patients with metastatic CRC receiving fixed doses of regorafenib or fruquintinib may experience more toxicities due to commonly having lower body surface area compared to White patients.
Clinical Trial Evolution Needed
The limitations of current clinical trial designs highlight the need for more inclusive approaches. Benjamin L. Schlechter, MD, a medical oncologist at Dana-Farber Cancer Institute, emphasized concerns about data collection practices and the need to study real differences in patient responses.
"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," Schlechter said.
The integration of real-world evidence with clinical trial data enables more personalized treatment decisions. As Bekaii-Saab explained, "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. 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."
This complementary approach becomes increasingly important as treatment options expand and the need for precision medicine grows in colorectal cancer care.
