ASCO: Expanded genetic testing should be standard for metastatic colorectal cancer

ASCO released a provisional clinical opinion update recommending that all patients with metastatic colorectal cancer who are candidates for anti-EGFR antibody therapy undergo KRAS and NRAS expanded genetic testing.

The report indicated that an analysis of outcomes from 15 phase 2 and 3 trials showed patients with RAS mutations are unlikely to benefit from anti-EGFR monoclonal antibody therapy alone or in combination with chemotherapy.

Carmen J. Allegra

Thus, patients should undergo expanded testing, or assessment of KRAS and NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61) and exon 4 (codons 117 and 146).

“It is clear… that RAS testing is necessary before initiating treatment of patients who are considered candidates for anti-EGFR monoclonal antibody therapy because RAS mutations in exon 2, 3 or 4 are associated with lack of benefit from this treatment and may, in fact, be associated with worse outcomes when … added to chemotherapy,” Carmen J. Allegra, MD, chief of the division of hematology and oncology and professor of medicine at University of Florida Health Cancer Center, and colleagues of the ASCO provisional clinical opinion update committee, wrote.

“Restricting cetuximab [Erbitux, Lilly] or panitumumab [Vectibix, Amgen] administration to patients whose tumors have no RAS mutations detected will help further tailoring of therapy to maximize patient benefit while minimizing harm,” Allegra and colleagues added.

Two of the studies the committee reviewed provided data on extended RAS testing for both KRAS and NRAS mutations.

One of them, the phase 3 PRIME study, evaluated survival outcomes of the addition of panitumumab to FOLFOX4 chemotherapy.

In that study, RAS mutations as an inclusive group appeared associated with poorer PFS (median, 7.3 months vs. 8.8 months; P = .02) and OS (15.5 months vs. 19.3 months) in the panitumumab combination arm compared with FOLFOX4 alone. Douillard and colleagues also found that any RAS exon 3 (codon 59) mutation might be a negative predictor for panitumumab efficacy.

The second study, the phase 3 CRYSTAL trial, evaluated the addition of cetuximab to FOLFIRI chemotherapy. Van Cutsem and colleagues showed other RAS mutations detected were associated with a lack of benefit from the addition of cetuximab with regard to PFS (median, 7.4 months vs. 7.5 months) and OS (16.4 months vs. 17.7 months) among patients without mutations in codon 12 or 13 of KRAS exon 2. Patients without any RAS mutations detected experienced significant PFS (median 9.9 months vs. 8.4 months) and OS (23.5 months vs. 20 months; P ˂ .05 for both) benefits with the addition of cetuximab to chemotherapy.

These data stress the need for a wider-range of molecular analyses for metastatic colorectal cancer, according to the committee.

“In addition to RAS testing, other biomarkers are needed to determine the best treatment for patients with metastatic colorectal cancer, because the efficacy of anti-EGFR monoclonal antibody therapy, even in the RAS wild-type population, is modest,” Allegra and colleagues wrote. “We have yet to find predictive biomarkers to guide selection of the treatment most likely to benefit patients with metastatic colorectal cancer.” – by Anthony SanFilippo

References:

Allegra CJ. J Clin Oncol. 2015;doi:10.1200/JCO.2015.63.9674.

Douillard JY, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1305275.
Van Cutsem E, et al. J Clin Oncol. 2015; doi:10.1200/JCO.2014.59.4812.

Disclosure: One member of the provisional clinical opinion update committee reports consultant/advisory roles with Amgen, Intervention Insights, the Medical Research Council and Palmetto GBA. All other members report no relevant financial disclosures.