Time to look beyond wild-type KRAS in metastatic CRC?

CHICAGO – Molecular testing of patients with metastatic colorectal cancer for activating mutations in KRAS and NRAS oncogenes can help clinicians choose the most appropriate first-line therapy, findings of a mutational analysis study suggest.

In the CRYSTAL study, the addition of cetuximab (Erbitux) to the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) improved survival in patients with wild-type KRAS (codons 12 and 13 in exon 2) compared with FOLFIRI alone, but not those with mutations in KRAS exon 2.

The current study, a retrospective analysis of a subgroup of patients with wild-type KRAS who had mutations in other KRAS or NRAS exons, showed that any RAS mutation neutralized the benefit of cetuximab, reported Dr. Eric Van Cutsem of University Hospitals Gasthuisberg Leuven and KU Leuven, Belgium.

"I think it’s fair to say that exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type exon 2 treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI. We believe therefore that all patients with colorectal cancer should be treated for a full, extensive RAS analysis from today on, and that this marker testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment in patients with metastatic colorectal cancer," he said at the annual meeting of the American Society of Clinical Oncology.

Dr. Van Cutsem and his colleagues conducted an exploratory analysis looking at the treatment effect of adding cetuximab to FOLFIRI in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer.

BEAMing up RAS

They identified 430 patients with tumor samples evaluable for other RAS mutations using BEAMing (Beads, Emulsions, Amplification, Magnetics) technology. The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 molecules in plasma, according to the American Association for Cancer Research.

Among all 430 RAS evaluable patients, FOLFIRI plus cetuximab was associated with better progression-free survival (PFS; 11.3 vs. 7.7 months for FOLFIRI alone, hazard ratio [HR] 0.58, P = .0001), overall survival (OS; 26.1 vs. 20.2 months, HR 0.75, P = .0080), and objective response rate (ORR; 61.4% vs. 38.2%, HR 2.64, P less than .0001).

But in a subanalysis of the 63 patients (14.7%) with wild-type KRAS exon 2 but new RAS mutations in KRAS exons 3 and 4, or NRAS exons, 2, 3 and 4, they found that any RAS mutation appeared to nullify the benefit of adding cetuximab, with no significant differences between FOLFIRI with or without cetuximab in either PFS, OS, or ORR.

For example, for patients with RAS wild type, median PFS for those treated with FOLFIRI plus cetuximab was 11.4 months vs. 8.4 months for those treated with FOLFIRI only (HR 0.50, 95% confidence interval [CI] 0.41-0.76). But for patients with any RAS mutation, the PFS was 7.4 and 7.5 months respectively (HR 1.10, CI, 0.85-1.4).

Similarly, median overall survival among all RAS wild-type patients in the subgroup was 28.4 months vs. 20.2 months (HR 0.69, CI 0.54-0.88), but among those with any RAS mutation was 16.4 vs. 17.7 months (HR 1.05, CI, 0.86-1.28)

Although cetuximab did not benefit patients with RAS mutations, neither did it cause harm, as evidenced by a similar safety profile among RAS wild-type and mutant subgroups, Dr Van Cutsem said.

Evidence from this and five other clinical trials suggests that clinicians should not use epidermal growth factor receptor (EGFR) inhibitors in patients with tumors that harbor any RAS mutations, said Dr. Neal J. Meropol, chief of hematology and oncology at the University Hospitals Seidman Cancer Center at Case Western Reserve University, Cleveland.

"I view this as a four-star [out of five] recommendation. As each of the new mutations are rare, and real differences in biologic behavior and response to treatment are still possible within these rare sub [mutations]," he said.

Although the differences in outcomes between various studies may be attributable to the use of different testing platforms, "it seems very unlikely to me that the benefit of treatment in one of these rare [mutations] will be great enough to conclude that this is a high-value treatment for these patients. Further pooled analyses across studies are needed to provide additional insight into this question," he said.

The study was supported by Merck. Dr. Van Cutsem reported receiving research funding from Merck Serono. Dr. Meropol disclosed serving as consultant/adviser to Precision Therapeutics.

CHICAGO – Molecular testing of patients with metastatic colorectal cancer for activating mutations in KRAS and NRAS oncogenes can help clinicians choose the most appropriate first-line therapy, findings of a mutational analysis study suggest.

In the CRYSTAL study, the addition of cetuximab (Erbitux) to the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) improved survival in patients with wild-type KRAS (codons 12 and 13 in exon 2) compared with FOLFIRI alone, but not those with mutations in KRAS exon 2.

The current study, a retrospective analysis of a subgroup of patients with wild-type KRAS who had mutations in other KRAS or NRAS exons, showed that any RAS mutation neutralized the benefit of cetuximab, reported Dr. Eric Van Cutsem of University Hospitals Gasthuisberg Leuven and KU Leuven, Belgium.

"I think it’s fair to say that exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type exon 2 treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI. We believe therefore that all patients with colorectal cancer should be treated for a full, extensive RAS analysis from today on, and that this marker testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment in patients with metastatic colorectal cancer," he said at the annual meeting of the American Society of Clinical Oncology.

Dr. Van Cutsem and his colleagues conducted an exploratory analysis looking at the treatment effect of adding cetuximab to FOLFIRI in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer.

BEAMing up RAS

They identified 430 patients with tumor samples evaluable for other RAS mutations using BEAMing (Beads, Emulsions, Amplification, Magnetics) technology. The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 molecules in plasma, according to the American Association for Cancer Research.

Among all 430 RAS evaluable patients, FOLFIRI plus cetuximab was associated with better progression-free survival (PFS; 11.3 vs. 7.7 months for FOLFIRI alone, hazard ratio [HR] 0.58, P = .0001), overall survival (OS; 26.1 vs. 20.2 months, HR 0.75, P = .0080), and objective response rate (ORR; 61.4% vs. 38.2%, HR 2.64, P less than .0001).

But in a subanalysis of the 63 patients (14.7%) with wild-type KRAS exon 2 but new RAS mutations in KRAS exons 3 and 4, or NRAS exons, 2, 3 and 4, they found that any RAS mutation appeared to nullify the benefit of adding cetuximab, with no significant differences between FOLFIRI with or without cetuximab in either PFS, OS, or ORR.

For example, for patients with RAS wild type, median PFS for those treated with FOLFIRI plus cetuximab was 11.4 months vs. 8.4 months for those treated with FOLFIRI only (HR 0.50, 95% confidence interval [CI] 0.41-0.76). But for patients with any RAS mutation, the PFS was 7.4 and 7.5 months respectively (HR 1.10, CI, 0.85-1.4).

Similarly, median overall survival among all RAS wild-type patients in the subgroup was 28.4 months vs. 20.2 months (HR 0.69, CI 0.54-0.88), but among those with any RAS mutation was 16.4 vs. 17.7 months (HR 1.05, CI, 0.86-1.28)

Although cetuximab did not benefit patients with RAS mutations, neither did it cause harm, as evidenced by a similar safety profile among RAS wild-type and mutant subgroups, Dr Van Cutsem said.

Evidence from this and five other clinical trials suggests that clinicians should not use epidermal growth factor receptor (EGFR) inhibitors in patients with tumors that harbor any RAS mutations, said Dr. Neal J. Meropol, chief of hematology and oncology at the University Hospitals Seidman Cancer Center at Case Western Reserve University, Cleveland.

"I view this as a four-star [out of five] recommendation. As each of the new mutations are rare, and real differences in biologic behavior and response to treatment are still possible within these rare sub [mutations]," he said.

Although the differences in outcomes between various studies may be attributable to the use of different testing platforms, "it seems very unlikely to me that the benefit of treatment in one of these rare [mutations] will be great enough to conclude that this is a high-value treatment for these patients. Further pooled analyses across studies are needed to provide additional insight into this question," he said.

The study was supported by Merck. Dr. Van Cutsem reported receiving research funding from Merck Serono. Dr. Meropol disclosed serving as consultant/adviser to Precision Therapeutics.

CHICAGO – Molecular testing of patients with metastatic colorectal cancer for activating mutations in KRAS and NRAS oncogenes can help clinicians choose the most appropriate first-line therapy, findings of a mutational analysis study suggest.

In the CRYSTAL study, the addition of cetuximab (Erbitux) to the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) improved survival in patients with wild-type KRAS (codons 12 and 13 in exon 2) compared with FOLFIRI alone, but not those with mutations in KRAS exon 2.

The current study, a retrospective analysis of a subgroup of patients with wild-type KRAS who had mutations in other KRAS or NRAS exons, showed that any RAS mutation neutralized the benefit of cetuximab, reported Dr. Eric Van Cutsem of University Hospitals Gasthuisberg Leuven and KU Leuven, Belgium.

"I think it’s fair to say that exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type exon 2 treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI. We believe therefore that all patients with colorectal cancer should be treated for a full, extensive RAS analysis from today on, and that this marker testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment in patients with metastatic colorectal cancer," he said at the annual meeting of the American Society of Clinical Oncology.

Dr. Van Cutsem and his colleagues conducted an exploratory analysis looking at the treatment effect of adding cetuximab to FOLFIRI in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer.

BEAMing up RAS

They identified 430 patients with tumor samples evaluable for other RAS mutations using BEAMing (Beads, Emulsions, Amplification, Magnetics) technology. The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 molecules in plasma, according to the American Association for Cancer Research.

Among all 430 RAS evaluable patients, FOLFIRI plus cetuximab was associated with better progression-free survival (PFS; 11.3 vs. 7.7 months for FOLFIRI alone, hazard ratio [HR] 0.58, P = .0001), overall survival (OS; 26.1 vs. 20.2 months, HR 0.75, P = .0080), and objective response rate (ORR; 61.4% vs. 38.2%, HR 2.64, P less than .0001).

But in a subanalysis of the 63 patients (14.7%) with wild-type KRAS exon 2 but new RAS mutations in KRAS exons 3 and 4, or NRAS exons, 2, 3 and 4, they found that any RAS mutation appeared to nullify the benefit of adding cetuximab, with no significant differences between FOLFIRI with or without cetuximab in either PFS, OS, or ORR.

For example, for patients with RAS wild type, median PFS for those treated with FOLFIRI plus cetuximab was 11.4 months vs. 8.4 months for those treated with FOLFIRI only (HR 0.50, 95% confidence interval [CI] 0.41-0.76). But for patients with any RAS mutation, the PFS was 7.4 and 7.5 months respectively (HR 1.10, CI, 0.85-1.4).

Similarly, median overall survival among all RAS wild-type patients in the subgroup was 28.4 months vs. 20.2 months (HR 0.69, CI 0.54-0.88), but among those with any RAS mutation was 16.4 vs. 17.7 months (HR 1.05, CI, 0.86-1.28)

Although cetuximab did not benefit patients with RAS mutations, neither did it cause harm, as evidenced by a similar safety profile among RAS wild-type and mutant subgroups, Dr Van Cutsem said.

Evidence from this and five other clinical trials suggests that clinicians should not use epidermal growth factor receptor (EGFR) inhibitors in patients with tumors that harbor any RAS mutations, said Dr. Neal J. Meropol, chief of hematology and oncology at the University Hospitals Seidman Cancer Center at Case Western Reserve University, Cleveland.

"I view this as a four-star [out of five] recommendation. As each of the new mutations are rare, and real differences in biologic behavior and response to treatment are still possible within these rare sub [mutations]," he said.

Although the differences in outcomes between various studies may be attributable to the use of different testing platforms, "it seems very unlikely to me that the benefit of treatment in one of these rare [mutations] will be great enough to conclude that this is a high-value treatment for these patients. Further pooled analyses across studies are needed to provide additional insight into this question," he said.

The study was supported by Merck. Dr. Van Cutsem reported receiving research funding from Merck Serono. Dr. Meropol disclosed serving as consultant/adviser to Precision Therapeutics.