ASCO Releases Provisional Recommendation for RAS Testing in mCRC

Carmen J. Allegra, MD

ASCO has recommended extended RAS testing as a predictive biomarker of response for anti—EGFR monoclonal antibodies, further stressing the importance of broader molecular analyses for patients with metastatic colorectal cancer (mCRC), according to a joint provisional statement published in the Journal of Clinical Oncology.¹

The endorsement was based on findings from 15 analyses that evaluated outcomes with expanded testing in phase II and III clinical trials for the EGFR antibodies cetuximab (Erbitux) and panitumumab (Vectibix). The overwhelming theme of the evidence showed that patients with RAS-mutated mCRC had inferior outcomes with anti—EGFR therapy.

In the expanded RAS testing, KRAS exon 2 (codons 12 and 13) mutations are assessed in addition to alterations in KRAS exons 3 (codons 59 and 61) and 4 (codons 117 and 146) along with NRAS exon 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146). This testing should be completed prior to the administration of an anti—EGFR therapy, the recommendation noted, given a lack of benefit with these therapies in those harboring RAS alterations.

“The weight of current evidence indicates that anti-EGFR monoclonal antibody therapy should only be considered for treatment of patients whose tumor is determined to not have mutations detected after such extended RAS testing," lead author Carmen J. Allegra, MD, and colleagues wrote in the provisional clinical opinion. “Restricting cetuximab or panitumumab administration to patients whose tumors have no RAS mutations detected will help further tailoring of therapy to maximize patient benefit while minimizing harm.”

A draft of the provisional clinical opinion was released in late March, and was compiled by ASCO, the College of American Pathologists (CAP), the American Society for Clinical Pathology (ASCP), and the Association for Molecular Pathology (AMP). A public comment period for the guideline ended on April 22, 2015.

Prior to this opinion, the NCCN guidelines had already recommended that cetuximab and panitumumab should only be utilized in patients with KRAS/NRAS wild-type mCRC. Additionally, in early March 2015, based on a growing body of evidence, the FDA expanded the label for panitumumab to be specifically indicated for the treatment of patients with RAS wild-type mCRC, further solidifying a continued shift toward an expanded testing strategy.

The decision to expand the label for panitumumab was based on an analysis of the phase III PRIME study, which was published in The New England Journal of Medicine in 2013.² This same study was also analyzed for the ASCO testing recommendation and was 1 of 2 studies that contained data on both NRAS and KRAS.

In the study, the median overall survival (OS) with panitumumab plus FOLFOX4 was 26.0 months compared with 20.2 months with FOLFOX4 alone in patients with wild-type RAS mCRC (HR, 0.78; P = .04). The progression-free survival (PFS) in patients without RAS mutations was 10.1 months with panitumumab/FOLFOX4 compared with 7.9 months with FOLFOX4 alone (HR, 0.72, 95% CI, 0.58-0.90; P = .004).

The phase III CRYSTAL trial was the second study analyzed for the ASCO recommendation with both KRAS and NRAS data available.³ In this study, additionally RAS mutations beyond KRAS exon 2 were detected in 14.7% of patients.

In the expanded RAS analysis, the median OS with cetuximab plus FOLFIRI was 28.4 months compared with 20.2 months with FOLFIRI alone in patients with wild-type RAS mCRC (HR, 0.69; 95% CI, 0.54-0.88). The PFS in patients without RAS mutations was 11.4 months with cetuximab/FOLFIRI compared with 8.4 months with FOLFIRI alone (HR, 0.56, 95% CI, 0.41-0.76).

“It should be noted that because the subgroups of patients with any of the less common RAS mutations are small (representing approximately 2% of all CRCs), there is inadequate evidence to provide a definitive opinion as to the potential lack of benefit for the use of anti—EGFR antibodies for patients whose cancer harbors any specific RAS mutation other than codon 12 or 13 KRAS mutation,” the authors noted. “As such, the less common mutations have been considered as a group and, as a group, seem to confer the same lack of benefit as seen with the more common codon 12 and 13 mutations in exon 2 of KRAS.”

The RAS testing provisional clinical opinion is part of a larger guideline that is being developed by ASCO, CAP, AMP, and ASCP for all GI tumor markers. The full guideline is anticipated to be published in the second quarter of 2016 and is expected to include guidance on testing for BRAF, PTEN, PIK3CA and other genes.

"In addition to RAS testing, other biomarkers are needed to determine the best treatment for patients with mCRC, because the efficacy of anti-EGFR monoclonal antibody therapy, even in the RAS wild-type population, is modest," the authors wrote. "We have yet to find predictive biomarkers to guide selection of the treatment most likely to benefit patients with mCRC."

In the draft guideline issued earlier this year, deficient mismatch repair/microsatellite instability (dMMR/MSI) testing was recommended in all patients for prognostic stratification and identification of Lynch syndrome. Additionally, the guideline called for BRAF V600 mutational analysis for some patients with mCRC, although the genes status was not deemed a predictive marker for response to anti-EGFR inhibitors.

References

1. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti—Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015 [Published online October 5, 2015]. J Clin Oncol. doi: 10.1200/JCO.2015.63.9674.
2. Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab—FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med. 2013;369:1023-1034.
3. Van Cutsem E, Lenz H-J, Köhne C-H, et al. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer [Published online January 20, 2015]. J Clin Oncol. doi: 10.1200/JCO.2014.59.4812.