Certainly, the RAS findings constitute only a single chapter of the anti-EGFR antibody selection story.
—Brandon G. Smaglo, MD
In an important post hoc analysis (reviewed in this issue of The ASCO Post), Van Cutsem and colleagues have further refined our knowledge of who are the “right” patients with metastatic colorectal cancer to receive treatment with cetuximab (Erbitux).1 This refinement was accomplished through the retrospective assessment of extended RAS profiling on the patients’ tumors from the original CRYSTAL study, to assess for a correlation between additional RAS mutations and cetuximab benefit.
First Foray Into ‘Personalized’ Therapy
When the association was first identified between KRAS mutational status and tumor response to antiepidermal growth factor receptor antibody (anti-EGFR) therapy, both cetuximab and panitumumab (Vectibix), it represented the first instance in which a therapy for patients with metastatic colorectal cancer could be recommended based upon unique characteristics of the individual tumor. In essence, it was the first foray into “personalized” therapy for colorectal cancer.2,3 This updated analysis from the CRYSTAL study further refines this personalization. In doing so, however, it also further reduces the percentage of patients available to benefit from this therapy.
As noted in the study article, a similar finding of extended RAS mutational analysis from the PRIME study tumors identified a corresponding lack of benefit with the use of panitumumab to extended RAS mutations.4 The immediate impact from this analysis of the CRYSTAL study, as well as the PRIME study analysis, is the need for extended RAS evaluation of all colorectal tumors in patients for whom treatment with either anti-EGFR monoclonal antibody is being considered.
The CRYSTAL authors do note that their patient numbers were insufficient to make a definitive statement for extended RAS testing, but the trend toward a lack of benefit is adequate to make this practice change. Although this will translate into fewer patients who are eligible to receive cetuximab, the corollary effect may be that the group selected is even more appropriate for such treatment, and thus the benefit may be greater for this select population.
No One-Size-Fits-All Model of Agent Selection
Beyond any discussion of cetuximab, this analysis is also illustrative of the wider variation between tumors and their resultant susceptibility to various treatments, thus giving further argument against a one-size-fits-all model of agent selection. Of the nine currently approved systemic agents for the treatment of metastatic colorectal cancer in the United States, the two anti-EGFR monoclonal antibodies remain the only drugs that are selected for or excluded from use based upon further analysis of the individual tumor. All others are used in an appropriate sequence, based in part on the discretion and comfort of the treating physician, with a common credo applied that all patients should, at some point in their treatment course for metastatic disease, receive every drug.
Barring any contraindication, this usually means that for the first and second lines of therapy, patients are treated with a fluoropyrimidine-based chemotherapy doublet combined with a biologic agent. There is no guidance yet available as to whether that doublet should initially employ irinotecan or oxaliplatin, and from the efficacy point of view, the doublet regimens FOLFOX (fluorouracil-oxaliplatin) and FOLFIRI (fluorouracil-irinotecan) have demonstrated equivalence.5 For those patients with RAS wild-type tumors, there is no guidance as to whether the biologic treatment should consist of an anti-EGFR or an anti-VEGF (vascular endothelial growth factor) antibody; data presented at the plenary session of the 2014 ASCO meeting suggested neither biologic was superior.6
Nevertheless, as suggested by the further refinement of RAS status and anti-EGFR antibody effect from the analyses of the CRYSTAL and PRIME data, the most effective chemotherapy doublet and biotherapy selection could be personalized in the future, by using the unique features of the individual tumors rather than some uniformly applicable standard.
More on Tumor Profiling
To arrive at this point of personalization, we first need to know what these unique features are that we are looking for with each drug; in other words, using CRYSTAL as an example, one could ask what is the “RAS” for all of the other agents? Complicating this search is the question as to what level of the metabolome (genomic, proteomic, etc) will contain these treatment-guiding tumor features. In all probability, the answer again will be diverse, spanning the metabolome as opposed to residing within one layer of it. Moreover, it is naive to think that the answer will reside in a simple, single “yes-or-no” reference point within this network. Rather, it will rely on the dynamic interplay throughout the network. Certainly, the RAS findings constitute only a single chapter of the anti-EGFR antibody selection story.
Tumor profiling to guide treatment selection is one of the hottest topics in cancer research right now, and a number of different tumor-profiling techniques are under development. At present, such tools must be used with caution, providing an additional piece of information to be considered rather than a definitive map to be followed. However, in the future, they hold the promise of evolving into that map, guiding patients and their oncologists to optimal therapies for their unique cancer. As our understanding of the biomarkers and other unique drivers of individual cancers becomes more refined, it is hoped that we can extend the work done by Van Cutsem and colleagues to all cancer therapies, selecting what is truly the hand-chosen “right” drug for the unique tumor. ■
Disclosure: Dr. Smaglo reported no potential conflicts of interest.
1. Van Cutsem E, Lenz HJ, Köhne CH, et al: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33:692-700, 2015.
2. Van Cutsem E, Köhne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408-1417, 2009.
3. Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol 28:4697-4705, 2010.
4. Douillard JY, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1034, 2013.
5. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 23:4866-4875, 2005.
6. Venook AP, Niedzwiecki D, Lenz HJ, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. 2014 ASCO Annual Meeting. Abstract LBA3.
Dr. Smaglo is Assistant Professor of Medicine at The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC.
The phase III CRYSTAL trial showed that the addition of cetuximab (Erbitux) to first-line FOLFIRI (fluorouracil, leucovorin, and irinotecan) significantly improved overall survival, progression-free survival, and objective response rates in patients with KRAS codon 12/13 (exon 2) wild-type...