More Mutations Predict Resistance to Colorectal Cancer Therapy

A new study shows that additional RAS mutations can confer resistance to panitumumab, an epidermal growth factor receptor (EGFR) antibody approved for the treatment of metastatic colorectal cancer (CRC). The study evaluated the efficacy of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) by KRAS, NRAS, and BRAF mutation status in the first-line, phase III PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) study. The results are published in the New England Journal of Medicine.

A wild-type RAS gene status does not mean that a patient will respond to treatment with an anti-EGFR antibody, noted Leonard Saltz, MD, head of the colorectal oncology section at Memorial Sloan-Kettering Cancer Center in New York, who was not involved with the current study.

The study shows that there is a wider spectrum of RAS-mutated tumors that do not respond to treatment with EGFR antibodies. This could at least partly explain the fraction of patients who, though not harboring a KRAS mutation in exon 2, have previously not responded to anti-EGFR treatment.

But, the data is based on an exploratory analysis and is not yet definitive. The study authors cautioned that these new progression-free and overall survival analyses based on mutation status are retrospective, and conclusions based on this update may be limiting. Further trials or analyses of pooled data from anti-EGFR trials will be needed to confirm these results.

The benefit of the combination therapy is increased if patients with other RAS and BRAF mutations besides those with the KRAS mutation in exon 2 are excluded, according to the results by Jean-Yves Douillard, MD, PhD, of the Institut de Cancérologie de l'Ouest in Nantes, France, and colleagues. Five hundred and twelve patients (out of a total of 1,060 patients) had no detectable RAS mutation. For these patients, adding panitumumab to a FOLFOX4 regimen improved progression-free survival by 2.2 months (10.1 months vs 7.9 months; P = .004). Panitumumab also improved overall survival by 5.8 months (26 months vs 20.2 months; P = .04). The improvement in overall survival in this exploratory analysis is significant, the study authors conclude.

The TheraScreen assay was utilized to assess the exon 2 KRAS mutation status of tumors, using fixed tumor samples. PCR and DNA sequencing from these tumor samples were used to identify any mutations in the RAS or BRAF genes.

In the original report of the PRIME trial, patients were put into two groups: those harboring a KRAS mutation in exon 2 and those without a KRAS mutation in exon 2. Based on this data, patients without a mutation in exon 2 (but not excluding other RAS mutations) had a significant improvement in progression-free survival (9.6 months vs 8 months; P = .02).

One hundred and eight of 620 patients (17%) for which the RAS mutation status could be evaluated had a RAS mutation that was not in exon 2 of the KRAS gene. These RAS mutations were associated with a worse progression-free and overall survival compared with patients with wild-type RAS genes, consistent with the results seen for exon 2 KRAS-mutated patients. Patients with a mutation other than in exon 2 treated with the combination had a progression-free survival of 7.3 months compared with 8.8 months for those treated with FOLFOX alone (P = .02). The current updated analysis showed that the difference in overall survival between wild-type patients and those with a mutation other than a KRAS mutation in exon 2 was significant (P = .01).

A V600E BRAF mutation was identified in 9% (53 of 620) of patients, which did not overlap with KRAS or NRAS mutations. These BRAF-mutated patients had similar progression-free and overall survival whether they received FOLFOX alone or in combination with panitumumab, but the number of patients with a BRAF mutation was relatively small.

Two epidermal growth factor receptor (EGFR) antibodies-panitumumab and cetuximab-are approved for metastatic CRC. Studies in both treatment-naive and pretreated advanced CRC patients have shown that patients whose tumors have specific mutations in exon 2 of the KRAS gene do not respond to EGFR inhibitors. Patients with metastatic CRC who are eligible for an EGFR inhibitor should be treated with either panitumumab or cetuximab, but not switched from one to the other upon progression, said Saltz.

Approximately 40% of patients have a KRAS mutation. “All metastatic CRC patients should have KRAS testing performed on their tumor,” said Saltz. But, for Saltz, the mutation status does not impact his first choice for first-line treatment, as he prefers to treat metastatic CRC first with chemotherapy rather than an EGFR inhibitor.

“In my opinion, panitumumab is not something that should be used in first-line treatment of metastatic CRC,” said Saltz. The only patients who benefit from EGFR inhibitors such as panitumumab are those who get a substantial skin rash. “I prefer to save EGFR agents such as panitumumab or cetuximab for third-line therapy when other options have been exhausted.”

Previous studies have identified additional mutations in either KRAS or NRAS that do not overlap with KRAS mutations in exon 2, suggesting that all of these mutations may have similar functions.