EARLY RESPONSE AS PROGNOSTIC FACTOR IN COLORECTAL CANCER

Early tumor shrinkage may aid clinicians in determining which patients with metastatic colorectal cancer (mCRC) are more likely to receive survival benefit from targeted therapy, say investigators in a study published online in the Journal of Clinical Oncology.

An analysis of combined data from 2 large randomized trials comparing common chemotherapy regimens with or without cetuximab (Erbitux, Bristol-Myers Squibb/Lilly) showed that, among patients with KRAS wild-type tumors, early tumor shrinkage of 20% or greater in tumor diameters was associated with both longer progression-free and overall survival (PFS and OS), report Hubert Piessevaux, MD, and colleagues from the Cliniques Universitaires Saint-Luc in Brussels, Belgium.

"The association was much stronger in patients with KRASwild-type tumors than in those with KRAS mutations, which may reflect the sensitivity of these [wild type] tumors to cetuximab plus chemotherapy," the authors write.

Previous research has established that patients with the tumor genotype known as KRAS wild-type may respond to cetuximab, an antiepidermal growth factor receptor therapy, while those with KRAS mutations either do not respond or have negative outcomes.

Thus, clinicians need to determine the KRAS mutation status of a colorectal cancer before using cetuximab.

Now, the new findings suggest that observation of a patient's "response phenotype" rather than tumor genotype alone may be the better approach for selecting appropriate therapy, comment Geoffrey R. Oxnard, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, and Lawrence H. Schwartz, MD, from Columbia University College of Physicians & Surgeons, in New York, in anaccompanying editorial.

"Yes, this new biomarker [early tumor shrinkage] deserves independent validation before widespread adoption. However, this work represents the beginning of a period in which, for those therapies without adequate predictive tissue biomarkers, response phenotype plays an increasing role in guiding our delivery of targeted therapies," they write.

CRYSTAL and OPUS

The Belgian investigators combined prospective data from the phase 3 CRYSTAL trial comparing the FOLFIRI regimen (fluorouracil, leucovorin, and irinotecan) plus cetuximab with FOLFIRI alone, and the phase 2 OPUS trial comparing FOLFOX-4 (fluorouracil, leucovorin, and oxaliplatin) plus cetuximab with FOLFOX-4 alone. Both trials enrolled patients with mCRC to receive frontline combination therapy. A total of 1289 patients were included in the analysis.

In both trials, patients with KRAS ­wild-type tumors who received chemotherapy and cetuximab had the most pronounced degree of tumor shrinkage. In contrast, patients with tumors bearing KRAS mutations derived little if any benefit from the addition of cetuximab to combination chemotherapy.

In multivariate analysis controlling for baseline variables and treatment and stratified by KRAS mutation status, early tumor shrinkage (that is, within 8 weeks of the start of therapy) was significantly associated with both PFS and OS.

In CRYSTAL, each 10% decrease in tumor size was associated with a hazard ratio (HR) of 0.782 (95% confidence interval [CI], 0.749 to 0.816) for PFS, and an HR of 0.896 (95% CI, 0.870 to 0.923) for OS. In OPUS, for the same measure, the HR for PFS was 0.836 (95%CI, 0.793 to 0.881) and for survival was 0.855 (95% CI, 0.810 to 0.901).

20% Shrinkage Bodes Well

The authors determined that a cutoff value of 20% early tumor shrinkage or greater compared with less than 20% could identify patients who were receiving chemotherapy with cetuximab who had both longer PFS and OS.

"If confirmed in a prospective trial, [early tumor shrinkage] may be useful to guide on-treatment decisions including continuation or discontinuation of therapy. The cutoff values for such decisions will depend on the clinical context in which they are used. For example, implementation of a 20% cutoff would allow the selection of a subgroup of approximately two-thirds of patients with KRAS wild-type tumors, with a median survival of 30 months when treated with FOLFIRI plus cetuximab," Dr. Piessevaux and colleagues write.

In their editorial, Dr. Oxnard and Dr. Schwartz say that the study suggests several potential applications, including response-guided therapy (for example, to indicate that a therapeutic switch may be warranted in patients with nonshrinking tumors).

The findings also suggest that early tumor shrinkage may be a valid clinical biomarker in patients receiving combination chemotherapy with cetuximab.

"On the basis of the data shown in the article by Piessevaux et al, one could argue that added toxicity without evidence of response is not worth continued cetuximab and that chemotherapy alone would be adequate,” the editorialists write.

At the same time, robust early tumor shrinkage could help clinicians and patients stay the course with therapy, even when side effects emerge.“One could advocate for continued cetuximab and aggressive rash management if a patient with similar toxicity exhibited a 40% decrease in tumor diameter," they add.

The funding source for the study was not disclosed. Hubert Piessevaux disclosed receiving honoraria from Merck Serono. Two of the coauthors are employees of Mercj KGaA of Germany. Other authors had various potential conflict of interest disclosures: Geoffrey R. Oxnard disclosed compensation for serving as a consultant/advisor to Genentech; Lawrence H. Schwartz disclosed compensation for consulting with GlaxoSmithKline, BioClinica, and ICON Medical, and honoraria from Novartis.