Second-Line Cetuximab Shows PFS Benefit in Wild-Type mCRC

Fortunato Ciardiello, MD, PhD

Patients with metastatic colorectal cancer (mCRC) benefited from treatment with cetuximab plus chemotherapy even after disease progression on a similar regimen as long as their tumors did not harbor mutations in any of four key genes, according to research findings presented at the 2015 World Congress on GI Cancer.

The CAPRI-GOIM study found that participants whose tumors had no mutation in the KRAS, NRAS, BRAF, and/or PIK3CA genes experienced significantly prolonged progression-free survival (PFS) by continuing cetuximab as part of a second-line regimen compared with chemotherapy alone, reported lead author Fortunato Ciardiello, MD, PhD.

In the quadruple wild-type population, the median PFS was 6.9 months for patients (n = 34) who received the cetuximab-containing regimen compared with 5.3 months for participants (n = 32) who received chemotherapy alone (HR, 0.56; 95% CI, 0.37-0.94; log-rank test, P = .025).

By contrast, the addition of cetuximab to chemotherapy failed to benefit patients with mutations. Patients with mutations in any of the four genes had median PFS of 2.7 months with the cetuximab regimen (n = 19) versus 4.4 months among participants (n = 32) who received chemotherapy alone (HR, 1.70; 95% CI 0.94-3.05; P = .07).

“The most important thing we found was that we had two patient populations: one that was multiple wild type and normal for all four genes and another with mutations in at least one of these genes,” said Ciardiello, a medical oncologist at Seconda Università degli Studi di Napoli in Italy.

“Those patients with tumors which were multiple wild type were most likely to be EGFR-dependent; these patients had significantly better PFS when treated with cetuximab and chemotherapy than when treated with chemotherapy,” Ciardiello said. “Response rate was also improved, as was overall survival.”

He added a “word of caution” for managing patients with any of the four mutations. “These results generate a very important signal—that treatment with cetuximab following progression in patients with mutations in these four genes has a detrimental effect,” he said.

Molecular Analysis Unfolds

The FDA has approved cetuximab, a monoclonal antibody that inhibits EGFR, as first-line therapy for patients with KRAS wild-type, EGFR-expressing tumors in combination with FOLFIRI (leucovorin, fluorouracil, irinotecan).

Although this regimen has become the standard of care for patients with mCRC KRAS and NRAS wild-type tumors, no data were available on the role of continuing cetuximab therapy after progression, Ciardiello and colleagues noted in their conference abstract. The phase II CAPRI-GOIM study was designed to determine whether cetuximab would improve outcomes upon progression if added to FOLFOX (leucovorin, fluorouracil, oxaliplatin).

In all, the study enrolled 340 patients with mCRC and KRAS exon 2 wild-type tumors, according to local laboratory assessment. All patients received FOLFIRI plus cetuximab until disease progression or unacceptable toxicity.

Following first-line treatment, patients experiencing disease progression were randomized 1:1 to receive FOLFOX plus cetuximab (n = 74) or FOLFOX (n = 79). The primary endpoint was PFS.

Results in the overall population showed a nonstatistically significant advantage in PFS favoring the cetuximab group; median PFS was 6.4 months in the cetuximab-containing arm compared with 4.5 months in the chemotherapy-alone group (HR = 0.81; P = .19).

“We therefore looked for patient characteristics that would account for this result. Next-generation sequencing of the genes of interest was performed on the archival tissue samples from the patients’ primary tumors,” explained Ciardiello.

Sequencing was possible in 117 patients (76.5%). The analyses revealed that 66 patients had no mutations in KRAS, NRAS, BRAF, or PIK3CA genes and 51 patients had tumors mutated in at least one of these genes. KRAS exon 2 mutations were found in 27.4% of the tumors that were originally identified as wild type, PIK3CA was mutated in 1.8% of tumors, BRAF in 6.0%, and NRAS in 8.5%.

When results were reanalyzed according to mutational status, patients with quadruple wild-type tumors experienced the greatest benefit not only in PFS but also in other measures.

Among patients with quadruple wild-type tumors, the median overall survival (OS) was 23.7 months with cetuximab compared to 19.8 months with chemotherapy alone (HR, 0.57; P = .56). The rate of progressive disease (PD) with the cetuximab regimen was 17.6% compared with 28.1% for chemotherapy alone.

For patients with mutations in any of these genes, median OS was 11.6 month in the cetuximab group versus 14.0 months in the chemotherapy arm (HR, 1.60; P = .10). PD rates were 52.6% in the cetuximab group versus 34.4% for chemotherapy alone.

Discussant Michel Ducreux MD PhD, of Institut Gustave Roussy, Villejuif, France, who was not involved in the study, said the findings demonstrate a further role for cetuximab in mCRC. “These results indicate an increased rate of response with cetuximab in second-line in patients with nonmutated tumors,” he said. “These are the first data showing that continuation of anti-EGFR inhibition could be an option in second-line in selected patients. Also, the results show that a deleterious effect can be avoided.”

Ciardiello said the treatment regimen should be studied further. “CAPRI is the first study to evaluate cetuximab as second-line in patients with mCRC. Results suggest continuing anti-EGFR treatment while switching the chemotherapy backbone in second-line is feasible and deserves to be explored in a larger, randomized, phase III study. Also, identifying patients whose tumor is EGFR dependent, also identifies patients responsive to this treatment,” he concluded.

Ciardiello F, Normanno N, Martinelli E, et al. Cetuximab beyond progression in RAS wild type (WT) metastatic colorectal cancer (mCRC): the CAPRI-GOIM randomized phase II study of FOLFOX versus FOLFOX plus cetuximab. Presented at: 2015 World Congress on GI Cancer; July 1-5, 2015; Barcelona, Spain. Abstract LBA09.

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