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.)

Given the lack of benefit (and some data suggest a negative effect) and the high cost – both financial and toxicity – of these agents, the National Comprehensive Cancer Network (NCCN) has amended their Guidelines for colon and rectal cancers to recommend the use of Erbitux and Vectibix only in mCRC patients with wild-type KRAS. Additionally, in Europe, Vectibix’s initial approval label was restricted to use in KRAS wild-type patients; Erbitux’s label was amended in July 2008 to restrict its use to KRAS wild-type patients in all lines of therapy, and the recent positive Committee for Medicinal Products for Human Use (CHMP) opinion for Vectibix in combination with systemic therapy was limited to patients with wild-type KRAS. The U.S. FDA followed suit in 2009 by adding a recommendation to the existing labels for both drugs that they only be used in patients with wild-type KRAS.

According to a survey by Kantar Health for Treatment Architecture, 92% of physicians reported that they are testing for the presence of KRAS mutations at some point in the treatment of their CRC patients; this nearly universal use of KRAS testing is similar to practices in Western Europe and Japan, and reflects both the widespread availability of the KRAS mutational test in these developed countries and awareness of the need to test patients.

However, mutations in KRAS exon 2 are not the only possible mutations in this gene.  Moreover, although the use of KRAS exon 2 testing identifies patients who are likely to have a response to anti-EGFR therapy, a fraction of these patients do not benefit from this treatment. In order to understand this, a retrospective analysis of the PRIME study evaluated the additional benefit one might observe in the use of an increased definition of having a KRAS mutation.

PRIME randomized 1,183 previously untreated patients to receive FOLFOX or FOLFOX plus Vectibix. In the original presentation (Douillard, J  Clin Oncol, 2010) and as presented in Table 2 above, the benefit of Vectibix was identified only in patients with KRAS wild-type (in exon 2).  However, PRIME also prospectively planned, following patients forward, to study all RAS mutations based on the retrospective analysis done on KRAS mutations. This was based on stratification of other mutations in KRAS as well as mutations in NRAS. The inclusion of other KRAS mutations as screening has repercussions: the inclusion of requiring these other sites to also be wild-type improved the hazard ratio for progression or death with the combination therapy from 0.80 to 0.72, indicating a lower chance of an event occurring. More importantly, progression-free survival was not improved by Vectibix in patients who were KRAS exon 2 wild-type but had mutations in other parts of KRAS (HR 1.28). Data such as this helped reinvigorate the examination of biomarker in CRC (Douillard, NEJM, 2013).

The Phase II PEAK Study, which was  presented at the ASCO 2013 annual meeting, evaluated Vectibix not only in mCRC patients with wild-type KRAS exon 2 but also in patients wild-type for exons 3 and 4 of KRAS and exons 2, 3 and 4 for NRAS. This study compared Vectibix plus mFOLFOX6 or Avastin plus mFOLFOX6 in 285 randomly assigned patients. In the KRAS wild-type exon 2 intent-to-treat group, progression-free survival was not significantly different between the two arms (HR 0.62, p=0.353). Median overall survival was significantly better in the Vectibix arm over the Avastin arm (34.2 months versus 24.3 months, HR 0.62, p=0.009).

In the wild-type RAS subgroup (defined as KRAS having no mutations in exons 2, 3 and 4 as well as being NRAS wild-type), progression-free survival and overall survival favored the Vectibix arm over the Avastin arm. Progression-free survival was improved by the addition of the targeted therapy (HR 0.65, p=0.029), and the benefit of targeted therapy was still apparent for overall survival (41.3 months versus 28.9 months, HR 0.63, p=0.058; Schwartzberg, J Clin Oncol, 2014). Findings such as these led to a continued push to understand how far-reaching these observations are, leading to several exploratory retrospective analyses presented at the ASCO 2014 meeting.

The Evolving Story of the RAS Family of Mutations   

Using the tumor samples evaluable for RAS mutation status from the original intent-to-treat study populations of the OPUS, CRYSTAL and PRIME studies, retrospective analyses were performed and presented at the ASCO 2014 annual meeting. The study question for these retrospective analyses was, “What is the influence on EGFR-inhibitor treatment outcome of other identified activating mutations at other exons within KRAS or NRAS?” These studies hypothesized that the KRAS exon 2 mutation is not the only biomarker in the RAS family with important treatment implications for mCRC patients.

In the OPUS study, the intent-to-treat population (n=337) was randomized to FOLFOX4 and Erbitux or FOLFOX4 alone. This first-line treatment study showed that in KRAS exon 2 wild-type patients’ response and progression-free survival were significantly improved. However, in the KRAS exon 2 mutant population, the addition of Erbitux was negatively associated with the treatment outcome (Bokemeyer, Ann Oncol, 2011). In a continued analysis of these data (Bokemeyer, Abstract  3505, ASCO 2014), mutation status was evaluable in 118 of 179 (66%) patients. In those with RAS wild-type tumors, response was significantly improved by the addition of Erbitux to FOLFOX4 (57.9% versus 28.6%, p=0.008). New RAS mutations were detected in 31 of 118 (26%) patients. In KRAS exon 2 wild-type patients who had these other KRAS mutations, the addition of Erbitux was associated with a lack of benefit (mean progression-free survival: 7.5 months versus 7.4 months, HR 0.77, p=0.60). 

The CRYSTAL study added further strength to the analysis of OPUS as well as PRIME. Adding Erbitux to FOLFIRI also significantly improved progression-free survival, overall survival and response in the first-line treatment of patients with KRAS exon 2 wild-type (Van Cutsem, NEJM, 2009). In a further retrospective analysis of the CRYSTAL data, mutational status was evaluated in all evaluable KRAS exon 2 wild-type tumors from (430 of 666, or 65%) patients. 

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