Patients with metastatic colorectal cancer (mCRC) who carry RAS mutations do not benefit when panitumumab (Vectibix, Amgen Inc.) is added to standard chemotherapy. By contrast, patients with mCRC who have no RAS mutations experience improvements in progression-free survival (PFS) and overall survival (OS).
This PRIME (Panitumumab Randomized Trial In Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) study included 1,183 patients with mCRC who were randomized and evaluated for KRAS exon 2.
KRAS mutation in exon 2 is a predictive biomarker for resistance to anti-epidermal growth factor receptor (EGFR) therapy, and panitumumab is an EGFR antagonist. This international, multicenter, prospective-retrospective analysis assessed the efficacy of panitumumab plus FOLFOX4 (oxaliplatin, fluorouracil and leucovorin) versus FOLFOX4 alone, as per RAS (either KRAS or NRAS) or BRAF mutation status.
Investigators hypothesized that other RAS mutations might also be predictive of successful or adverse treatment outcomes. Using DNA from tumor specimens banked during the PRIME study, analyses were conducted for mutations in KRAS exons 3 and 4; NRAS exons 2, 3 and 4; and BRAF exon 15. The rate of ascertainment for mutations was 89% (1,047 samples). The primary end point was PFS; secondary end points were OS and safety.
The study, headed by Jean-Yves Douillard, MD, PhD, and Kelly S. Oliner, PhD, and published in The New England Journal of Medicine (2013;369:1023-1034, PMID: 24024839), found that treatment effects differed between the mutation subgroups. Patients without RAS mutations (512) had an improved PFS (10.1 vs. 7.9 months) when FOLFOX4 was supplemented with panitumumab (hazard ratio [HR] for progression or death, 0.72; 95% confidence interval [CI], 0.58-0.90; P=0.004). OS was 26.0 months for the combination therapy versus 20.2 months for FOLFOX4 therapy alone (HR, 0.78; 95% CI, 0.62-0.99; P=0.04).
There were 108 patients (17%) who did not have mutated KRAS exon 2 but had other RAS mutations. In these patients, PFS and OS were also negatively affected, in line with the results from patients with KRAS mutations in exon 2. Additionally, BRAF mutations were also identified as a negative prognostic factor.
This study highlights the significant importance of mutation analysis when developing patient treatment plans.
Marwan Fakih, MD|
Professor of Oncology,
Section Head, GI Medical Oncology,
Department of Medical Oncology of Experimental Therapeutics,
City of Hope,
In a preplanned prospective-retrospective analysis, Douillard and colleagues recently reported an updated efficacy analysis of the PRIME study (FOLFOX vs. FOLFOX plus panitumumab) by RAS and RAF tumor status. RAS mutation was defined as the presence of exon 2, 3, and 4 KRAS or NRAS mutations (codons 12, 13, 61, 117 and 146). This expanded RAS signature identifies an additional 17% of patients who are RAS-mutant but lack an exon 2 KRAS mutation. Subgroup analyses suggest a detrimental effect on PFS and OS in the panitumumab arm in patients with KRAS exon 2 mutations and other non-KRAS exon 2 RAS-mutant patients. In contrast, the addition of panitumumab to FOLFOX in patients lacking any RAS mutation had a significant improvement in PFS (HR, 0.72; improvement in median PFS of 2.4 months) and OS (HR, 0.77; improvement in median OS of 5.4 months). The improvement in PFS and OS widened further on the panitumumab arm (HR, 0.68 and 0.74, respectively) upon excluding BRAF-mutant patients in the RAS wild-type population.
The validity of RAS-mutation signature as a predictive marker of response to anti-EGFR therapy also has been supported by the retrospective analyses of several other randomized clinical trials. Particularly, the FIRE-3 Phase III clinical trial of first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab versus FOLFIRI plus bevacizumab, presented at the European Cancer Congress in 2013, demonstrated a statistically significant improvement in OS in favor of the cetuximab arm.1 Patients with tumors lacking any RAS mutation experienced a statistically superior response rate (76% vs. 65.2%) and OS (33.1 vs. 25.9 months). However, the lack of improvement in PFS on FIRE-3 remains puzzling and suggests a potential role for depth or response in affecting OS. In contrast, patients with non-exon 2 KRAS mutations or NRAS mutations trended toward a worse clinical outcome on the cetuximab arm. The value of RAS status as a marker of response to anti-EGFR agents was recently reported in the PEAK trial (FOLFOX + panitumumab vs. FOLFOX + bevacizumab in the first-line treatment of metastatic colorectal cancer) and study 20020408 (panitumumab vs. BSC [best supportive care] in refractory colorectal cancer).2,3
The reproducibility of RAS status as a predictive marker of benefit from anti-EGFR agents across the PRIME and FIRE-3 studies validates RAS testing as a new standard for anti-EGFR therapy selection in the front-line treatment of mCRC. RAS mutations are estimated to occur in 52% of patients with CRC, narrowing anti-EGFR candidacy to less than 50% of the patients with mCRC. Given the low frequency of NRAS mutation and non-exon 2 KRAS mutations in CRC, the ability to conduct prospective clinical trials to validate the predictive value of each individual mutation is not clinically feasible. The American Society of Clinical Oncology and the National Comprehensive Cancer Network previously recommended the exclusion of exon 2 KRAS-mutant CRCs from anti-EGFR therapy based on retrospective data analyses from the OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of mCRC), CRYSTAL (Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer), 20020408 study, and NCI-CO17 clinical trials.4,5 PRIME and FIRE-3 provide no less compelling data of the predictive value of NRAS and low-frequency non-exon 2 KRAS mutations vis-à-vis anti-EGFR therapy. As clinical oncologists, we have a clinical obligation to avoid exposing patients to unnecessary toxicities and futile therapies. Both PRIME and FIRE-3 suggest a trend to a worse clinical outcome in KRAS exon 2 wild-type/RAS-mutant patients, supporting the prompt need to exclude these patients from anti-EGFR therapy.
As important, the exclusion of patients with RAS mutations identifies a population with a robust clinical benefit from the addition of anti-EGFR therapy in the first-line setting. The PRIME study showed an improvement in OS of 5.4 and 7.4 months with addition of panitumumab to FOLFOX in RAS wild-type and RAS/BRAF wild-type patients, respectively. Improvement of more than 7 months in OS was similarly noted with FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in RAS wild-type patients in the FIRE-3 study.1 These are clinically significant improvements in OS that have not been attained with any other biologic agent in the first-line treatment of mCRC in combination with FOLFOX or FOLFIRI, arguably the most commonly used cytotoxic regimens. PRIME and FIRE-3 clearly position anti-EGFR therapy as a favored approach in patients without RAS mutations when FOLFOX or FOLFIRI are contemplated. Note that no randomized Phase III clinical trials to date have shown any survival advantage to the addition of bevacizumab in combination with FOLFOX or FOLFIRI in the first-line treatment of mCRC.6-8
Based on the data presented here, we have now incorporated an expanded RAS mutation assay for all of our mCRC patients before consideration of anti-EGFR therapy. We consider patients without RAS and BRAF mutations to be optimal candidates for the incorporation of anti-EGFR therapy in combination with FOLFOX or FOLFIRI. However, we recognize that such a strategy requires careful considerations for the potential acute and long-term dermatologic and electrolyte toxicities associated with panitumumab or cetuximab. As anti-EGFR therapy moves to the front-line management of mCRC in the community, more efforts need to be made to further expand on the current RAS predictive signature and to develop strategies to reduce undesirable skin toxicities.
- Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3. European Cancer Congress, 2013. Abstract E17-7073.
- Schwartzberg LS, Rivera F, Karthaus M, et al. Analysis of KRAS/NRAS mutations in PEAK: a randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC). J Clin Oncol. 2013;31(suppl; abstr 3631).
- Patterson S, Peeters M, Siena S, et al. Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408). J Clin Oncol. 2013;31(suppl; abstr 3617).
- Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091-2096, PMID: 19188670.
- Benson AB 3rd, Bekaii-Saab T, Chan E, et al. Metastatic colon cancer, version 3.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2013;11:141-152; quiz 152, PMID: 23411381.
- Passardi A, et al. Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the Itaca randomized clinical trial. J Clin Oncol. 2013;31(suppl; abstr 3517).
- Saltz L, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). Gastrointestinal Cancers Symposium 2007.
- Stathopoulos GP, Batziou C, Trafalis D, et al. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78:376-381, PMID: 20798560.
Dr. Fakih reported no relevant financial disclosures.