BEACON trial in colorectal cancer is “single worst reported,” says critic

Redactions

The open label phase III trial in patients who had metastatic colorectal cancer with the BRAF V600E mutation was presented during an oral session at the 2019 European Society for Medical Oncology conference at the end of September and was simultaneously published online in the New England Journal of Medicine,2 although at the time of publication some parts of the study protocol were redacted.

In the trial 665 patients were assigned to triple therapy of binimetinib, encorafenib, and cetuximab, to double therapy of encorafenib and cetuximab, or to a control group. For patients in the control group the investigators decided whether to treat them with cetuximab and irinotecan or with cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan).

The reported median overall survival was 9.0 months in the triple therapy group and 5.4 months in the control group (hazard ratio for death 0.52 (95% confidence interval 0.39 to 0.70) P<0.001).

However, the study did not say what proportion of patients in the control group were treated with each of the two options. Prasad further criticised the choice of control as flawed because cetuximab has no role in BRAF V600 metastatic colorectal cancer.

Basic questions

The trial was funded by Array BioPharma, Merck (for sites outside the United States), ONO Pharmaceutical, and Pierre Fabre. The report of the results said that the manuscript was drafted with “professional medical writing assistance funded by Array BioPharma.” Prasad said that it read more like a press release than a scientific paper and did not answer basic questions that doctors would want to know.

“This is the worst trial I have ever read,” said Prasad in the podcast. “I don’t understand how a trial could be so poorly reported and be missing such basic information.”

For example, he criticised the study for not including the full inclusion and exclusion criteria. The authors said that these were in the attached trial protocol; however, these sections were originally redacted. Other redacted information included the secondary endpoints of the trial, the statistical plan, and how the researchers had tested for the BRAF mutation.

The large number of blacked out sections in the protocol made it “look like the Mueller report,” said Prasad. He asked how it could be that the people enrolled in a study, what had happened to them, and how you judged success were somehow proprietary.

Incorrect version

Since the podcast was broadcast and after being contacted by The BMJ, the New England Journal of Medicine updated the protocol without the redactions. A spokeswoman told The BMJ, “During the production process, an incorrect version of the protocol was inadvertently posted.”

However, Prasad said that interpreting the results required additional information still not provided in the paper, protocol, or supplement. He has written to the journal to ask a series of questions [box]. A spokeswoman for the New England Journal of Medicine told The BMJ that these were questions for the authors and not for the journal.

Prasad criticised the paper’s reviewers and the journal’s editorial judgment.

“This information is not rocket science. It is very basic information that is needed to make sense of the trial,” he told The BMJ. “Neither the authors, reviewers, nor editors have requested it be included in the paper. This baffles me. Does the New England Journal of Medicine want to print research reports or press releases?”

The authors of the paper sent a statement to The BMJ saying that they “stand by the design and results of the BEACON CRC trial, which we believe will form the basis for a new standard of care for patients with BRAF V600E mutant mCRC [metastatic colorectal cancer] who typically have a very poor prognosis.”