Sorting Out the Targeted-Agent Combinations for Colorectal Cancer

Dr. Pohl and colleagues have provided a comprehensive and well written overview of the current landscape of targeted agents and chemotherapy in advanced colorectal cancer. It is clear that we have made significant progress in the past decade, first with the development of oxaliplatin (Eloxatin)/irinotecan (Camptosar) combination chemotherapy, which has translated into a doubling and tripling of antitumor response rates in metastatic disease, and a near doubling of median survival in advanced disease. The advent of more active therapy in metastatic disease has also translated into a significant survival improvement in stage III disease, with the application of fluorouracil (5-FU)/oxaliplatin–based adjuvant chemotherapy.

These advances have been further extended with increases in response and survival demonstrated for the addition of agents targeting either the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) pathways. Whether the benefits for these targeted agents will extend to patients treated in the adjuvant setting, after curative surgery, awaits evaluation in ongoing trials in the United States and Europe.

Optimizing Treatment
We now have defined standards of care for the treatment of advanced colorectal cancer extending out to third-line therapies. Optimal treatment of each patient with metastatic colorectal cancer, however, needs to be individualized. Bevacizumab (Avastin) has emerged as an important component of all first-line chemotherapy, but it remains unclear if similar benefits are accrued with oxaliplatin- vs irinotecan-based first-line therapy, given the failure of the NO16966 trial to demonstrate response or overall survival benefits for the addition of bevacizumab to first-line oxaliplatin-based chemotherapy in advanced disease-despite an improvement in progression-free survival. Because efficacy in NO16966 may have been undercut by early termination of patient therapy due to oxaliplatin toxicity, this study underscores the care that must be used in first-line treatment of patients with oxaliplatin combination chemotherapy.

In particular, cumulative neurologic toxicity can be avoided by employing the strategy defined by the OPTIMOX-1 trial, in which patients had planned discontinuation of oxaliplatin after six cycles but continued with maintenance therapy with leucovorin/5-FU. This approach reduced neurologic toxicity and did not compromise therapeutic efficacy, indicating that a maintenance strategy of 5-FU alone (with bevacizumab) may be employed, after initial therapy with both 5-FU and oxaliplatin. At a minimum, patients treated with oxaliplatin in combination with 5-FU and bevacizumab who develop oxaliplatin toxicity should continue on therapy with 5-FU and bevacizumab alone, to optimize the potential benefit from treatment. Actual changes in therapy (to irinotecan or cetuximab [Erbitux]-based treatment) should be made only for disease progression.

Exploring Other Combinations
Data from the Eastern Cooperative Oncology Group (ECOG) E3200 trial, as well as retrospective data from the Bevacizumab Regimens Investigation of Treatment Effects and Safety (BRiTE) registry, provide compelling data to continue bevacizumab into second-line therapy. However, continuation of a costly agent into salvage therapy without demonstration of benefit from clearly designed clinical trials raises economic considerations.

The ongoing Intergroup SO600 trial addresses this issue. After progression on 5-FU/oxaliplatin/bevacizumab therapy, patients are treated with irinotecan-based chemotherapy, with or without the continuation of bevacizumab into second-line therapy. This trial is somewhat problematic, however, because all patients receive cetuximab as part of first-use irinotecan, based on the assumption that earlier use of cetuximab in this setting is justified. Although the small BOND 2 trial indicated that bevacizumab added to either cetuximab alone, or cetuximab in combination with irinotecan, resulted in improved response and progression-free survival, this approach has not been validated in a larger data set.

A possible negative interaction between EGFR and VEGF therapy has been shown by the PACCE trial, which indicated that the addition of the EGFR-targeted agent panitumimab (Vectibix) to 5-FU/oxaliplatin/bevacizumab resulted in inferior progression-free and overall survival, as well as greater toxicity. As we often learn from phase III trials, more is not always better, and sometimes it is worse.

Role of Cetuximab
Should cetuximab be routinely used as part of irinotecan-based chemotherapy? The CRYSTAL trial indicated that adding cetuximab to FOLFIRI (leucovorin/5-FU/irinotecan) improved response and progression-free survival in first-line therapy for advanced disease. The Erbitux Plus Irinotecan in Colorectal Cancer (EPIC) trial evaluated patients after progression of disease on 5-FU/oxaliplatin, and compared irinotecan alone vs irinotecan plus cetuximab. Although earlier use of cetuximab with irinotecan significantly improved response rate and progression-free survival, it did not improve overall survival, as irinotecan failures could cross over to receive cetuximab. The higher response rate indicates that earlier cetuximab use with irinotecan should be a consideration in patients with borderline or potentially resectable metastatic disease, or in patients with more symptomatic or rapidly progressive disease in whom a superior response early on may translate into a better palliative benefit.

Which targeted agents should be used first line in combination with chemotherapy-bevacizumab, cetuximab, or both? This question is now being addressed in the first-line Intergroup Trial XX, which compares first-line chemotherapy with FOLFOX (leucovorin/5-FU/oxaliplatin) or FOLFIRI in combination with bevacizumab, cetuximab, or both. Routine use of combination antibody therapy awaits evaluation in this trial, given the negative results seen with the PACCE combination antibody trial. This Intergroup trial also represents the only study performing a head-to-head comparison of cetuximab vs bevacizumab as part of first-line combination chemotherapy.

Looking Ahead
How can we best apply newer targeted agents in patient care? Emerging data indicate that the mutation of k-ras essentially abrogates any benefit for cetuximab in advanced disease patients, and this marker will now need to be evaluated in all ongoing trials of EGFR-targeted agents in colorectal cancer, in both the advanced-disease and adjuvant settings. With the likelihood of even more new and active targeted agents coming online for colorectal cancer, identifying which patients will most likely benefit from these agents will not only optimize their therapeutic impact, but also minimize the economic impact. The future is clearly bright in colorectal cancer, as therapeutic options on the horizon continue to improve and expand, offering hope to patients and to the physicians who care for them.

The main article can be found here:
Targeting Metastatic Colorectal Cancer in 2008: A Long Way From 5-FU