Treatment strategies for metastatic colorectal cancer (mCRC) are evolving towards more personalized approaches, incorporating novel combinations and targeted therapies to improve outcomes for patients who have progressed after initial treatment. Recent clinical trials, including CodeBreaK300, MOUNTAINEER, and SUNLIGHT, have presented data that are reshaping the treatment landscape and emphasizing the importance of molecular testing to guide therapeutic decisions.
Second-Line Therapies: Emphasizing Personalization
The CodeBreaK300 trial, presented at the 2024 ASCO Annual Meeting, evaluated the KRAS G12C inhibitor sotorasib in combination with the EGFR inhibitor panitumumab in patients with KRAS G12C-mutated mCRC who had not previously received a KRAS G12C inhibitor. The study compared sotorasib at doses of 960 mg or 240 mg daily with investigator's choice of trifluridine/tipiracil or regorafenib. Results indicated that the sotorasib 960-mg arm significantly improved median progression-free survival (PFS) to 5.8 months (95% CI, 4.2-7.5), compared to 2.0 months (95% CI, 1.9-3.9) in the control arm (HR, 0.46; 95% CI, 0.29-0.72).
Marwan G. Fakih, MD, who presented the CodeBreaK300 data, noted, "The ORR was 30.0% [95% CI, 18.3%-44.3%] for sotorasib 960 mg plus panitumumab, and the responses are durable. The duration of response [DOR] was 10.1 months [95% CI, 3.1-12.9+]."
For patients with RAS wild-type, HER2-positive unresectable CRC or mCRC, the MOUNTAINEER study investigated the combination of tucatinib plus trastuzumab. The final analysis, presented at the 2024 ASCO Annual Meeting, confirmed a confirmed ORR of 39.3% (95% CI, 28.8%-50.5%) with a median DOR of 15.2 months (95% CI, 8.9-20.5). The median PFS and OS were 8.1 months (95% CI, 4.2-10.2) and 23.9 months (95% CI, 18.7-28.3), respectively.
Al B. Benson III, MD, FACP, FACCC, FASCO, commented on the tolerability of the regimen, stating, "Some of the principal adverse effects [AEs] include fatigue, diarrhea, and nausea, as well as hypertension, as one would imagine with a TKI. Overall, it’s well tolerated."
Third-Line and Beyond: Sequencing and Efficacy
In later lines of therapy, options include regorafenib, trifluridine/tipiracil with or without bevacizumab, and fruquintinib. The phase 3 SUNLIGHT trial evaluated trifluridine/tipiracil with and without bevacizumab in patients who had progressed following treatment with a maximum of two prior chemotherapy-based regimens. The combination arm (n = 246) demonstrated a median OS of 10.8 months (95% CI, 9.4-11.8) compared to 7.5 months (95% CI, 6.3-8.6) with trifluridine/tipiracil alone (HR, 0.61; 95% CI, 0.49-0.77; P < .001).
Subgroup analyses of the SUNLIGHT trial presented at the 2024 Gastrointestinal Cancers Symposium (ASCO GI) and the 2024 ASCO Annual Meeting further defined the role of the SUNLIGHT regimen. One analysis examined the effect of trifluridine/tipiracil in combination with bevacizumab vs trifluridine/ tipiracil alone in patients younger than 65 years, patients aged 65 to 74 years, and those of at least 75 years of age. The hazard ratios for OS were 0.65 (95% CI, 0.48-0.87), 0.64 (95% CI, 0.43-0.94), and 0.49 (95% CI, 0.27-0.90), respectively, all of which were in favor of the combination arm.
Fruquintinib has also shown promise in the third line and beyond, as demonstrated in the FRESCO and FRESCO-2 trials. In the global FRESCO-2 trial, patients who received fruquintinib (n = 461) achieved a median OS of 7.4 months (95% CI, 6.7-8.2) compared with 4.8 months (95% CI, 4.0-5.8) in the placebo arm (n = 230; HR, 0.66; 95% CI, 0.55-0.80; P < .0001).
Kristen K. Ciombor, MD, MSCI, highlighted the importance of considering prior treatment sequences when using fruquintinib, noting, "I typically use trifluridine/tipiracil and bevacizumab prior to fruquintinib, with the exception being possibly in patients who have cytopenias who need to recover."
