No Harm, and Maybe Benefit, From Waiting for RAS Status in CRC

Liam Davenport

October 29, 2018

MUNICH — Clinicians who treat patients with metastatic colorectal cancer can safely wait to receive results of RAS mutation status before adding anti–epidermal growth factor receptor (EGFR) treatment to chemotherapy in the second or third cycle.

In fact, doing so appeared to improve some outcomes when compared to treating patients immediately with an anti–vascular endothelial growth factor (VEGF) drug, although the overall survival rates were similar.

This is the conclusion from a retrospective analysis, which should reassure both clinicians and their patients, say the authors.

Lola-Jade Palmieri, MD, a gastroenterologist at Hôpital Cochin, Paris, France, and colleagues assessed whether waiting for RAS status results before starting anti-EGFR treatment was associated with worse outcomes in comparison with starting treatment immediately with an anti-VEGF drug. It can take 20 days to receive RAS status results.

The study included more than 260 patients with metastatic colorectal cancer. The investigators found that delaying treatment while awaiting the test results did not affect outcomes.

Indeed, patients for whom anti-EGFR treatment was delayed while they underwent chemotherapy had significantly longer progression-free survival (PFS) and a better objective response rate than patients who received anti-VEGF treatment straightaway. There was no difference in survival.

"Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option compared to the immediate introduction of anti-VEGF," the team concludes.

The study was presented as a poster here at the European Society for Medical Oncology (ESMO) 2018 Congress.

In an interview, Palmieri told Medscape Medical News that the findings mean that clinicians "don't have to ask the anxious question, 'Should I start anti-EGFR treatment immediately for my patient, because I have a long time to wait for the RAS status.' "

Asked whether she thought the delay in receiving the results could be shortened, she pointed out that the wait time now is the same as when the test was introduced in 2010.

She said that in France, RAS status is assessed in certain centers that have the platforms available for analysis. The delay includes the time it takes for the sample to be transported to the center and then the time it takes for the test to be performed.

Palmieri added: "Even if everyone says it has to be shorter, it's really difficult to make it shorter.

"I think this will change maybe with circulating tumor DNA testing, but right now, it has been like 7 or 10 years we've had these delays, so I do not think it's going to get shorter," she commented.

Study Details

In their poster, the team explained that first-line treatment of unresectable metastatic colorectal cancer in patients who have an RAS/BRAF wild-type mutation can be doublet chemotherapy with either an anti-VEGF or an anti-EGFR drug.

More than half of patients with metastatic colorectal cancer have a KRAS or an NRAS mutation at presentation. Several studies have demonstrated the prognostic value of RAS mutations with respect to response to anti-EGFR treatment.

Although these results support determining RAS status before starting anti-EGFR treatment, in practice, this leads to delays in treatment while waiting for the test results. One study found that the median time to receive results regarding RAS status was 20 days.

To determine the impact of delaying anti-EGFR drugs in the first-line treatment of metastatic colorectal cancer, the team gathered data from 22 teaching hospitals, four cancer centers, and two general hospitals in France.

They included all patients with nonresectable colorectal cancer for whom a KRAS and an NRAS mutation test had been requested between 2013 and 2015 and who had not already received chemotherapy at the metastatic stage.

After screening, the team included 262 patients. Of these, 129 patients underwent doublet chemotherapy and anti-VEGF treatment without delay, and 133 underwent doublet chemotherapy, with anti-EGFR drugs being added in the second or third cycle.

The team noted that anti-EGFR treatment was introduced at the second cycle in 70% of patients and at the third cycle in 30% of patients.

The median time from RAS status request to receiving the result was 19 days (range, 13 - 26 days).

Patients treated with anti-VEGF drugs without delay were more likely to be male than those in the delayed anti-EGFR group, at 68% vs 56% (P = .048). They were also more likely to have >1 metastatic site, at 57% vs 40% (P = .02).

To account for this, the researchers created a propensity score that took into account metastatic sites to ensure that the two groups were comparable.

Duriong a median follow-up of 37.9 months, the objective response rate was higher for patients in the delayed anti-EGFR group than for those in the ant-VEGF group, at 66.7% vs 45.6% (P = .0007).

In addition, PFS was significantly longer for patients with left-sided colorectal cancer who underwent delayed anti-EGFR treatment, at 13.8 vs 10.8 months (hazard ratio, 0.69; P = .003).

There was no significant improvement in PFS with delayed anti-EGFR vs delayed anti-VEGF treatment for right-sided colorectal cancer, and there was no significant difference in overall survival between the groups, regardless of tumor location.

Regarding toxicities for which the incidence was >10%, the patients who underwent delayed anti-EGFR had more cutaneous adverse effects (P < .0001), whereas the patients who underwent delayed anti-VEGF treatment had more hemorrhagic events (P = .0007).

The team concluded that the "delayed introduction of anti-EGFR was not associated with a decrease in overall survival and PFS compared to the immediate introduction of anti-VEGF with chemotherapy."

No funding for the study was reported. Dr Palmieri has disclosed no relevant financial relationships. Two coauthors have reported relationships with pharmaceutical industries, as detailed in the abstract.

European Society for Medical Oncology (ESMO) 2018 Congress. Abstract 485P, presented October 21, 2018.

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