A phase 2 randomized clinical trial published on September 18, 2023 in JAMA Network Open evaluated the efficacy and safety of maintenance therapy with single-agent cetuximab after induction chemotherapy with FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus cetuximab for patients with RAS wild-type metastatic colorectal cancer (mCRC).
The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux) study was conducted from January 15, 2014 to November 23, 2018 at 35 sites in France. It was supported by Merck Serono and the Ligue Nationale Contre le Cancer. The study aimed to assess whether maintenance cetuximab could improve progression-free survival compared to observation alone after initial combination chemotherapy.
This multicenter, open-label trial enrolled 214 patients with unresectable RAS wild-type mCRC. Key inclusion criteria were histologically confirmed nonresectable mCRC, at least one measurable target lesion per RECIST v1.1 criteria, RAS wild-type status (locally assessed), ECOG performance status of 2 or less, and adequate organ function. Patients were excluded if they had received any prior chemotherapy except in the adjuvant setting more than 6 months prior, had brain metastases, or had other clinically relevant comorbidities.
All patients initially received 8 cycles of induction therapy with FOLFIRI plus cetuximab. Those without disease progression after induction (139 patients) were then randomized 1:1 to receive either maintenance cetuximab every 2 weeks (67 patients) or observation only (72 patients). The primary endpoint was 6-month progression-free rate from randomization.
Demographic data showed the median age of randomized patients was 66 years (range 23-85), with 68.3% being male. About half (51.5%) had an ECOG performance status of 0. The majority (78.3%) had left-sided primary tumors. Just over half (52.9%) had only one metastatic site, while 74.8% had synchronous metastases at diagnosis.
After a median follow-up of 40.5 months, the 6-month progression-free rate was 38.8% in the cetuximab maintenance group compared to only 5.6% in the observation group. Median progression-free survival (PFS) from randomization was 5.3 months with cetuximab maintenance versus 2.0 months with observation. Median overall survival from randomization was 24.8 months and 19.7 months in the cetuximab and observation groups, respectively.
The most frequent grade 3 or higher adverse event during the maintenance phase was rash, occurring in 11.9% of patients receiving cetuximab. No unexpected safety issues emerged during maintenance therapy.
In an exploratory molecular analysis, the presence of any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with significantly shorter PFS from randomization, regardless of treatment group (hazard ratio 1.63, p=0.04). This effect persisted even after excluding BRAF V600E and RAS mutations.
The authors concluded that while the study did not meet its primary endpoint, it suggests clinically meaningful PFS and overall survival benefits associated with cetuximab maintenance therapy. However, they noted that maintenance cetuximab or treatment breaks after first-line FOLFIRI plus cetuximab therapy may be inappropriate for patients with MAPK-mutated tumors, regardless of primary tumor location.
There were some important limitations to consider. The authors acknowledged their hypothesis for the 6-month progression-free rate was overly optimistic. Additionally, when the study was designed, the prognostic effects of primary tumor location and BRAF V600E mutation status were unknown, so patients were not selected based on these now-important criteria. The trial also did not analyze microsatellite status, which is now used to determine candidacy for first-line immunotherapy in some patients.
The lack of a maintenance therapy comparator arm using fluoropyrimidine with or without bevacizumab, which is currently recommended in guidelines, is another limitation in interpreting the results. The authors also noted the study was not powered for formal statistical comparison between the treatment groups.
Despite these limitations, this trial provides important data on the potential role of anti-EGFR maintenance therapy in RAS wild-type mCRC. The results suggest cetuximab maintenance may be a viable option to extend chemotherapy-free intervals while maintaining disease control in selected patients.
The findings could impact clinical practice by supporting the use of cetuximab maintenance in patients who respond to initial FOLFIRI plus cetuximab therapy, particularly those without MAPK pathway mutations. However, the authors emphasize that patients with right-sided primary tumors and/or MAPK-activating mutations may not benefit from this approach.
The exploratory molecular analysis highlighting the prognostic importance of MAPK pathway mutations beyond just RAS and BRAF V600E is also noteworthy. This suggests more comprehensive molecular profiling, including assessment of other MAPK pathway alterations, may be valuable in guiding treatment decisions for mCRC patients.
The safety profile observed supports the feasibility of cetuximab maintenance, with manageable toxicities. This could allow patients to maintain quality of life during treatment breaks from more intensive combination chemotherapy regimens.
While not definitive, these results add to the growing body of evidence supporting maintenance strategies in mCRC. They align with other recent trials like COIN-B and PANAMA that have shown potential benefits of anti-EGFR maintenance approaches after oxaliplatin-based induction regimens.
Importantly, this study included a randomized anti-EGFR-free control arm, which has been lacking in some previous maintenance trials. This allows for a clearer assessment of the impact of cetuximab maintenance compared to treatment breaks alone.
The findings also highlight the heterogeneity of mCRC and the need for personalized treatment approaches based on both clinical and molecular factors. The differential outcomes observed based on MAPK mutation status underscore the importance of comprehensive biomarker testing to optimize patient selection for targeted therapies.
From a health economics perspective, the potential to extend chemotherapy-free intervals while maintaining disease control could have implications for resource utilization and cost-effectiveness of mCRC treatment. However, formal cost-effectiveness analyses would be needed to fully assess this impact.
For clinicians, these results provide additional evidence to consider when making decisions about maintenance therapy in RAS wild-type mCRC patients. While current guidelines recommend fluoropyrimidine with or without bevacizumab maintenance after oxaliplatin-based induction, this study suggests cetuximab monotherapy may be an option worth considering after FOLFIRI-based induction in appropriately selected patients.
The authors note that further studies are needed to better clarify which subgroups of patients will benefit most from anti-EGFR maintenance and to define optimal maintenance regimens based on molecular tumor characteristics. Larger trials powered for survival endpoints and including quality of life assessments would help further elucidate the role of this approach.
In conclusion, while not practice-changing on its own, this phase 2 trial provides valuable data on the potential efficacy and feasibility of cetuximab maintenance therapy in RAS wild-type mCRC. It highlights the importance of molecular profiling in guiding treatment decisions and sets the stage for larger, more definitive studies of targeted maintenance strategies in this patient population. Clinicians should consider these findings in the context of evolving mCRC treatment paradigms and the growing emphasis on personalized, biomarker-driven approaches to cancer care.
References
Boige V, Blons H, François E, et al. Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2023;6(9):e2333533. Published 2023 Sep 5. doi:10.1001/jamanetworkopen.2023.33533
