July 2014 Edition Vol.11, Issue 7

Beyond KRAS exon 2: Research at ASCO and Important Treatment Implications for Metastatic Colorectal Cancer

Beyond KRAS exon 2: Research at ASCO and Important Treatment Implications for Metastatic Colorectal Cancer (cont.)

New RAS mutations were detected in 63 of 430 (15%) of KRAS exon 2 wild-type patients. In those with RAS wild-type tumors, a significant benefit across all endpoints was associated with the addition of Erbitux to FOLFIRI (ORR: 66.3% versus 38.6%, p<0.0001; mean progression-free survival: 11.4 months versus 8.4 months, HR 0.56, p=0.0002; mOS: 28.4 months versus 20.2 months, HR 0.69, p=0.0024).

As in the OPUS study, in patients with wild-type KRAS in exon 2 but with mutations in other locations in KRAS or NRAS, no benefit from the addition of Erbitux to FOLFIRI was apparent in progression-free survival (7.2 months versus 6.9 months, HR 0.81, p=0.56) or overall survival (18.2 months versus 20.7 months, HR 1.22, p=0.50). The conclusions of the study were that patients with RAS wild-type tumors derived a marked benefit from the addition of Erbitux to FOLFIRI, while patients with any RAS tumor mutations did not benefit (Ciardiello, Abstract 3506, ASCO 2014).

Epidemiological Implications of the Other RAS Mutants among the KRAS exon 2 Wild-Types

The findings from these numerous retrospective analyses regarding the impact of extended RAS mutants on efficacy of EGFR monoclonal antibodies has significant epidemiological implications. A systematic review of the literature in Kantar Health’s CancerMPact® Biomarker Analysis Report finds that approximately 36% of U.S. CRC patients possess KRAS exon 2 mutations. This translates to nearly 18,000 mCRC patients in 2014 ineligible for first-line treatment with an anti-EGFR monoclonal antibody. However, the retrospective analyses from the trials described above suggests that 15% to 26% of the patients who are seemingly wild-type for KRAS (exon 2) in actuality possess other RAS mutations, raising the population of first-line mCRC patients who are unlikely to benefit from an EGFR inhibitor to somewhere between 22,675 to 26,383 in the U.S. in 2014, representing 45% to 53% of the treatment-eligible population. For a tumor as common as CRC, the percentage of patients not benefiting from a cutting-edge targeted therapy is considerable.

KRAS Discordance between Primary Site and Metastasis

In most cases, current clinical practice involves assessment of biomarker status on a biopsied or surgically resected tumor sample. This is done purely for feasibility and ease – but in reality, is evaluation of biomarker status in a solitary lesion telling us the whole story in a patient with disseminated disease?

Dr. Kopetz presented an abstract at ASCO 2014 that sought to determine whether KRAS biomarker status was consistent between various lesions in mCRC patients. In this study, sequencing was successfully completed on 115 pairs of primary and metastatic tissue. The concordance rate for KRAS mutation was 89%. However, chemotherapy treatment was associated with 3.5-times higher odds of discordance compared to patients who did not receive therapy between resection of primary and metastatic tumors (P = 0.008; Kopetz, Abstract 3509, ASCO 2014).

In another presentation, a cohort of 10 patients with tissue from the primary site and one or more metastases, samples were compared for presence of mutations and variant allele frequency. Analysis for the six patients with KRAS exon 2 mutation and one patient with NRAS mutation showed mutation persistence from the primary tumor to the metastasis. However, KRAS variant allele frequency differed between primary and metastases based on interval treatment. There was shown to be a 2.4-fold elevated allele frequency between the primary tumor and the metastasis in three mCRC wild-type KRAS exon 2 patients who received Erbitux as third-line therapy (Graham, Abstract 3510, ASCO 2014).

Based on these data, we are beginning to learn that the rates of KRAS discordance between primary and metastatic mutations may vary considerably and can be influenced by prior treatment. These studies highlight the importance of considering the entirety of the disease when treating a patient with mCRC. It is likely that other RAS mutation testing will also be subject to mutation status discordance between the primary tumor and metastasis in mCRC, as well as changing mutation clonal status over the course of therapy, all of which will have important treatment and prognostic ramifications.


At the ASCO 2014 annual meeting, further data were presented highlighting that anti-EGFR monoclonal antibodies are inactive not only in patients with exon 2 KRAS mutations, as originally reported, but in patients with a mutation in any part of KRAS or other RAS genes. Data from retrospective, exploratory analyses presented at the 2014 ASCO annual meeting, building upon past studies, suggest that it is not sufficient to test mCRC patients for KRAS exon 2 mutation status to determine which patients will gain a treatment benefit from EGFR inhibitors. More prospective studies are necessary. All RAS mutations need to be diagnosed and seemingly only those patients wild-type for all RAS genes should be treated with EGFR-inhibitors. While the European Medicines Agency (EMA) has already changed the label for Erbitux and Vectibix  to “exclude all RAS mutations,” the FDA still labels these agents as “excluding KRAS mutations.” There is now convincing evidence that the label in the U.S. should be restricted like the European label. Discussions to expand U.S. labelling are presumed to be under way.



About the Contributor

Julie Katz, MPH, M.Phil. is Associate Consultant, Global Oncology Epidemiology at Kantar Health

Arnold DuBell, Ph.D., is a Consultant at Kantar Health

Kantar Health is a leading global healthcare advisory firm and trusted advisor to the world’s largest pharmaceutical, biotech, and medical device and diagnostic companies. It combines evidence-based research capabilities with deep scientific, therapeutic and clinical knowledge, commercial development know-how, and marketing expertise to help clients launch products and differentiate their brands in the marketplace.

Kantar Health’s oncology-related offers include Oncology Conference Insight, client-directed oncology conference coverage that analyzes the most important research at significant oncology meetings; and

CancerMPact® Treatment Architecture, which assesses the current clinical management of cancer patients by site and stage for all treatment modalities.

If you would like us to act as catalysts for you, contact us at www.kantarhealth.com/contactus.

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