New biomarker data in metastatic colorectal cancer (mCRC) presented at ASCO 2014 showed clinical implications of RAS mutations. The influence of RAS mutations on testing and treatment patterns of mCRC has profound implications on a tumor’s behavior throughout the course of the disease.
The EGFR monoclonal antibodies, Erbitux® (cetuximab, Eli Lilly/Bristol-Myers Squibb/Merck KGaA) and Vectibix® (panitumumab, Amgen), have been shown to benefit patients with wild-type KRAS, but not patients with mutant KRAS exon 2. In Europe, both drugs’ labels were restricted to KRAS wild-type patients. The FDA recommended in 2009 that both drugs be used only in patients with wild-type KRAS.
To understand the implications of some KRAS exon 2 wild-type patients not benefiting from anti-EGFR therapy, a retrospective analysis of the PRIME study evaluated the benefit of increasing the definition of a KRAS mutation. PRIME randomized 1,183 previously untreated patients to FOLFOX or FOLFOX plus Vectibix. Vectibix’s benefit was seen only in patients with KRAS exon 2 wild-type. (Douillard, J Clin Oncol, 2010). PRIME followed patients forward, studying all RAS mutations, other mutations in KRAS, and mutations in NRAS. Expanding the definition of RAS wildtype to include other KRAS mutational sites as well as NRAS improved the HR for progression or death with combination therapy from 0.80 to 0.72. Progression-free survival was not improved by Vectibix in KRAS exon 2 wild-type patients who had other KRAS mutations in other exons (HR 1.28); (Douillard, NEJM, 2013).
The PEAK Study, presented at ASCO 2013, evaluated Vectibix in mCRC patients with wild-type KRAS exon 2 and in patients wild-type for exons 3 and 4 of KRAS, and in exons 2, 3 or 4 of NRAS. Comparing Vectibix plus mFOLFOX6 or Avastin plus mFOLFOX6, 285 patients were randomized. In the KRAS exon 2 wild-type intent-to-treat group, progression-free survival was not significantly different between the two arms (HR 0.62, p=0.353). In the extended RAS wild-type subgroup, patients on the Vectibix arm had a progression-free survival benefit (HR 0.65, p=0.029) compared to patients treated with the Avastin combination (Schwartzberg, J Clin Oncol, 2014).
Retrospective RAS mutation status tumor sample analyses were performed from the OPUS and CRYSTAL studies and presented at ASCO 2014. In the OPUS study, which evaluated FOLFOX4 plus Erbitux versus FOLFOX4 alone, Erbitux improved progression-free survival in KRAS exon 2 wild-type patients (Bokemeyer, Ann Oncol, 2011). Extended RAS mutations, beyond those in exon 2, were detected in 26% of patients. Extending this to consider both KRAS exon 2 and the extra possible mutation sites indicated further Erbitux benefit, as Erbitux had no benefit in KRAS exon 2 wild-type patients who possessed other KRAS mutations (median PFS: 7.5 months vs. 7.4 months, HR 0.77, p=0.60; Bokemeyer, Abstract 3505, ASCO 2014).
The CRYSTAL study, Erbitux and FOLFIRI was associated with a significantly improved progression-free survival benefit compared to FOLFIRI in patients with the KRAS exon 2 wild-type phenotype (Van Cutsem, NEJM, 2009). Extended RAS mutations beyond that of KRAS exon 2 were detected in 15% of KRAS exon 2 wild-type patients. In these extended RAS wild-type patients, a significant benefit was associated Erbitux and FOLFIRI; mean progression-free survival: 11.4 months versus 8.4 months, HR 0.56, p=0.0002. In patients with wild-type KRAS exon 2 but with mutations in other locations in KRAS or NRAS, there was no benefit from adding Erbitux to FOLFIRI in progression-free survival (7.2 months versus 6.9 months, HR 0.81, p=0.56; Ciardiello, Abstract 3506, ASCO 2014).
Kantar Health’s CancerMPact® Biomarker Analysis Report reports approximately 36% of US CRC patients possess KRAS exon 2 mutations. Nearly 18,000 mCRC patients in 2014 are ineligible for first-line treatment with an anti-EGFR monoclonal antibody. These trials’ retrospective analyses suggest that 15-26% of patients who are seemingly wild-type for KRAS exon 2 actually possess other RAS mutations. For a common tumor like CRC, the percentage of patients not benefiting from targeted therapy is considerable.
Also, discordance among tumor lesions has important testing implications. An ASCO 2014 presentation examined whether KRAS biomarker status was consistent between various lesions in mCRC patients. In 115 pairs of sequenced primary and metastatic tissue, the KRAS mutation concordance rate was 89%. Chemotherapy 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). A cohort of 10 patients showed that KRAS variant allele frequency differed between primary and metastases based on treatment. (Graham, Abstract 3510, ASCO 2014). RAS mutation testing will likely be subject to mutation status discordance between the primary tumor and metastasis in mCRC, with important treatment and prognostic ramifications.
Data at ASCO 2014 showed that anti-EGFR monoclonal antibodies are inactive in patients with KRAS exon 2 mutations and in patients with a mutation in any part of KRAS or other RAS genes. Retrospective analyses indicate that it is not sufficient to test mCRC patients for only KRAS exon 2 mutational status, but that all RAS mutations should be considered during pathological evaluation. Only patients who are wild-type for all RAS genes should be treated with EGFR-inhibitors. While the European Medicines Agency has already modified its authorization for Erbitux and Vectibix to exclude patients with any RAS mutations, the FDA still labels these agents for patients without KRAS exon 2 mutations. Discussions to expand the FDA label are presumed to be under way.
Submitted by Julie Katz, MPH, M.Phil., Associate Consultant, Global Oncology Epidemiology, Kantar Health and Arnold DuBell, Ph.D., Consultant, Kantar Health
 KRAS having no mutations in exons 2, 3 and 4 as well as being NRAS wild-type